|Myasthenia Gravis||Multiple Sclerosis||Parkinson's Disease||Alzheimer's Disease|
|Parkinson's Disease is a slowly progressive neurological disorder caused by the loss of dopamine-containing cells in the nigrostriatal pathway. Prominent symptoms involve motor function, but psychiatric complications may also occur.|
|Selecting the correct dosage of levodopa can be difficult, requiring the expertise of a physician experienced at treating this disorder. Levodopa and the other medications used to treat Parkinson's disease can also produce side-effects ranging from uncontrolled movements (dyskinesias) to psychiatric problems (e.g., hallucinations, paranoia).|
Levodopa/carbidopa therapy is usually highly effective for the first
2 to 5 years of treatment. After this time over half of the patients begin
experiencing a prominent on-off effect from their levodopa. Shortly after
taking the medication, the patient is fully ambulatory often showing hyperactivity
and dyskinesia. As the medication levels drop, the patient loses mobility
and returns to an akinesic state resembling untreated Parkinson's disease.
This on-off cycling effect prompts patients to request higher doses of
levodopa administered more frequently, but the medication exacerbates the
dyskinesias and can lead to psychiatric complications (e.g., agitation,
hyperactivity, paranoia) in many patients. Indeed, patients who responsible
for taking their own medication tend to take their levodopa more often
than prescribed by their physician, thus exacerbating the dyskinesias and
|Chronic treatment with dopamine agonists or with dopamine antagonists
actually increases the sensitivity of dopamine receptors. These conditions
are termed sensitization and supersensitivity, respectively
-- the two terms actually refer to the same condition produced by opposite
Changes in receptor sensitivity are probably related to the dopamine
system's attempt to regulate its own level of activity and may explain
why considerable dopamine-cell loss occurs before any clinical symptoms
emerge. Interestingly, enhanced dopamine sensitivity has also been suggested
to underlie some forms of mental illness (e.g., schizophrenia) and drug
Changes in the sensitivity of dopamine receptors complicates treatment and is most likely the cause of the dyskinesic and psychiatric side-effects seen with long-term management of Parkinson's disease. Experimental treatments have been explored that may prevent the changes in dopamine-receptor sensitivity and thereby prolong the usefulness of levodopa and other therapies (e.g., Pudiak & Bozarth, 1997).
More recently direct-acting dopamine agonists (e.g., bromocriptine, pergolide) have been used in patients unresponsive to levodopa and in patients showing a strong on-off effect. The original rationale for using direct-acting agonists was that after the levodopa loses effectiveness due to continued dopamine cell loss, the direct activation of postsynaptic receptors is necessary to obtain a therapeutic effect. Unfortunately, direct-acting dopamine agonists have strong side effects (e.g., nausea, confusion, delirium, psychosis) which limit their usefulness. Nonetheless, some physicians have recently suggested that the direct-acting agonists delay the development of the on-off and other side-effects and have recommended that they be used as the first choice in treating Parkinson's disease.
Both levodopa and direct-acting dopamine agonist therapies fail to slow the progression of the dopamine cell loss in the substantia nigra: eventually, these treatments become ineffective as more dopamine cell die. For these patients there is the possibility of participating in experimental brain surgery that may restore some of the dopamine cells.
National Institute of Neurological Disorders & Stroke: Parkinson's Disease Backgrounder
National Insttitue of Neurological Disorders & Stroke: Emotional and Cognitive Aspects Working Group
Update on Parkinson's Disease - April 15, 1999 - American Academy of Family Physicians
neurosurgery for Parkinson's disease