Selegiline hydrochloride is used as adjunctive therapy for the symptomatic treatment of parkinsonian syndrome in patients who exhibit a deteriorating response to levodopa/carbidopa therapy; selegiline is designated an orphan drug by the US Food and Drug Administration (FDA) for this condition.
Levodopa (with or without carbidopa) currently is the most effective drug for relieving the manifestations of parkinsonian syndrome. However, the effectiveness of levodopa decreases substantially after the third year of treatment, and manifestations of the disease may return to pretreatment levels after 6-7 years of levodopa therapy. Several types of motor fluctuations, including return of parkinsonian manifestations toward the end of an interdose period ('' wearing off'' effect), sudden loss of effectiveness that may last from 1 minute to an hour followed by an equally sudden return of effectiveness (''on-off'' phenomena), and sudden hypotonic freezing episodes, may occur in some patients during long-term levodopa therapy. When used in conjunction with levodopa/carbidopa, selegiline hydrochloride may provide additional therapeutic benefit in patients who currently are maintained on optimal dosages of levodopa, patients who are beginning to develop tolerance to levodopa, and patients who are experiencing ''end-of-dose'' failure on levodopa therapy.
In clinical studies used to establish efficacy, patients were eligible for inclusion if they had a history of idiopathic parkinsonian syndrome (i.e., syndrome was not induced by drugs, trauma, or a tumor or associated with some other neurologic disorder). In double-blind controlled studies in patients receiving optimum therapy for parkinsonism syndrome that included levodopa/carbidopa, addition of selegiline was more effective than placebo in the following outcome measures: decrease in the amount of ''off'' time, improvement in patient self-rating of therapeutic success, and reduction in levodopa dosage. In these studies, selegiline produced beneficial effects on other outcome measures including reduced ''end-of-dose'' akinesia, tremor, and sialorrhea; improved speech and dressing ability; and overall disability as assessed by walking and symptomatic improvement.
Selegiline therapy appears to be most beneficial when used during the early stages of the '' wearing off'' effect; patients exhibiting severe ''on-off'' phenomena during levodopa therapy and patients with advanced parkinsonian syndrome are less likely to benefit from selegiline therapy. In clinical studies, addition of selegiline to levodopa therapy was especially useful in improving ''end-of-dose'' motor fluctuations. Selegiline improved ''end-of-dose'' fluctuations in 50-63% of patients and early morning akinesia in 56% of patients treated in several studies. In clinical studies, selegiline improved mild ''on-off'' disabilities and freezing; however, selegiline is not useful in the management of severe ''on-off'' oscillations. In patients responding to selegiline therapy, resting tremor and facial expression are relieved more frequently than rigidity. Sustained improvement may last up to 4 years; however, some patients experience a reduction in benefit after about 8 months. In patients who were receiving optimum antiparkinsonian therapy, addition of selegiline allowed an average reduction in levodopa dosage of 10-30%.
The effect of selegiline on survival in patients with parkinsonian syndrome has not been determined. In one retrospective study, survival time from initiation of levodopa until death averaged 12 or 10.75 years in patients receiving selegiline and those not receiving the drug, respectively. However, in a prospective, randomized, open long-term study in patients with early parkinsonian syndrome (i.e., symptomatic patients in need of dopaminergic therapy but not receiving such therapy), 28% of patients receiving selegiline in combination with levodopa or 18% of patients receiving levodopa alone died over a mean 5.6-year follow-up period. While disability scores at 4 years' follow-up were similar in both groups, the largest difference in mortality rates between the two groups was in deaths caused by parkinsonian syndrome. In another retrospective review of a large US study in patients with early parkinsonian syndrome who received selegiline, the death rate in these patients was similar to that of age- and gender-matched US population without parkinsonian syndrome.
Levodopa may be used in conjunction with amantadine, a dopamine agonist (e.g., pramipexole, bromocriptine, pergolide, ropinirole), or anticholinergic agents in the management of parkinsonian syndrome. Whether concomitant administration of selegiline is more effective than other adjunctive agents in parkinsonian patients receiving levodopa has not been determined. Limited evidence indicates that adjuvant therapy with selegiline is as effective as bromocriptine or methixene in the management of parkinsonian syndrome; in these studies, selegiline therapy was better tolerated than bromocriptine or methixene therapy. Therapy with levodopa, selegiline hydrochloride, and a dopamine agonist has been used successfully in some patients; however, efficacy of this combination compared with therapy with levodopa alone has not been established.
Addition of selegiline to a therapeutic regimen in patients in whom parkinsonian syndrome has been induced by drugs, trauma, or a tumor, or is associated with some other neurologic disorder has not been systematically evaluated to date. Selegiline hydrochloride has been used in a limited number of patients with neuroleptic-induced extrapyramidal manifestations; selegiline may be useful in patients who do not respond to anticholinergic agents.
Selegiline also has been used as monotherapy in patients with newly diagnosed parkinsonian syndrome; however, the manufacturers state that there is no evidence from controlled studies indicating that the drug provides benefit in the absence of concurrent levodopa therapy.Levodopa is currently the most effective drug for relieving manifestations of parkinsonian syndrome and is considered by many clinicians to be the drug of choice for the management of idiopathic parkinsonian syndrome. Most clinicians delay introduction of symptomatic therapy until the patient begins to experience functional limitations. Because levodopa tends to be less effective with prolonged use, some clinicians initiate therapy with selegiline, amantadine, or a dopamine agonist. Results from placebo-controlled studies, using delay in onset of manifestations requiring levodopa therapy as the end point, indicate that selegiline delays the onset of disability in patients with early (i.e., less than 5 years) untreated idiopathic parkinsonian syndrome. In one large study, delay to initiation of levodopa therapy averaged 2 or 1.25 years in patients receiving selegiline or placebo, respectively. However, the initial benefit of selegiline therapy may not be sustained. Although it has been suggested that selegiline is ''neuroprotective'' (i.e., reduces the rate of progression of parkinsonian syndrome), whether the delay in the development of motor disability in patients receiving the drug is secondary to a neuroprotective effect on residual dopamine neurons or to symptomatic effects that mask detection of the underlying disability has not been determined. Because selegiline is well tolerated and possibly neuroprotective, some clinicians initiate therapy with selegiline in newly diagnosed parkinsonian patients, reserving levodopa or another agent (i.e., a dopamine agonist) until manifestations become severe enough to warrant more aggressive therapy.
Although it has been suggested that selegiline therapy may provide antidepressant benefit in patients with parkinsonian syndrome and associated depressive manifestations, dosages required for antidepressant activity may exceed those required for antiparkinsonian activity, and such dosages are associated with an increased risk of adverse effects. In addition, current evidence is too limited to recommend any specific antidepressant for use in patients with parkinsonian syndrome and associated depression.
Selegiline has been used with equivocal results for the palliative treatment of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia). In the largest double-blind, controlled study to date comparing selegiline, vitamin E, combined therapy with both drugs, and placebo in patients with moderately severe dementia of the Alzheimer's type, selegiline or vitamin E was more effective than combined therapy, and all therapies were more effective than placebo, in decreasing the rate of functional decline (e.g., delaying the onset of poor outcome such as death, need for institutionalization, loss of ability to perform basic living tasks, deterioration in clinical dementia rating) when analysis of the results was adjusted for differences in baseline values for the study groups, but not for unadjusted data. However, there was no evidence of improvement in function compared with baseline, and all groups showed similar rates of cognitive decline over 2 years. In addition, methodologic concerns about this study and the associated conclusions have been raised. Although several other smaller studies showed some evidence of benefit with selegiline therapy, some experts state that evidence of clinical benefit for the drug in patients with dementia of the Alzheimer's type currently is inconclusive. Other experts, however, state that despite limitations of current evidence, a trial with selegiline therapy may be considered for Alzheimer's patients with mild to moderate impairment, although comparable evidence of efficacy with vitamin E and a more favorable toxicity profile of the vitamin may make this agent preferable to selegiline. Additional study and experience are needed to define more precisely the role of selegiline in the management of Alzheimer's disease.