A wide variety of adverse mental effects have been reported, including depression, anxiety, agitation, insomnia, somnolence, sleep attacks, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. Such adverse effects are more common in patients taking levodopa in combination with a decarboxylase inhibitor rather than levodopa alone, presumably because higher levels are reached in the brain. They may be precipitated by intercurrent illness or surgery. It may be necessary to reduce or withdraw the medication. Several atypical antipsychotic agents that have low affinity for dopamine D2 receptors (clozapine, olanzapine, quetiapine, and risperidone; see Chapter 29) are now available and may be particularly helpful in counteracting such behavioral complications. Pimavanserin (34 mg daily), a selective serotonin 5-HT2A inverse agonist, is also helpful for treating the hallucinations and delusions of Parkinson’s disease psychosis and has recently been approved for use in the USA. It should not be used for dementia-related psychosis and should be avoided in patients with QT prolongation.
The dopamine dysregulation syndrome is characterized by compulsive overuse of dopaminergic medication as well as by other impulsive behaviors; such impulse control disorders are more common with dopamine agonists than levodopa and are discussed later. Management involves the close regulation of dopaminergic intake.
Punding designates the performance of stereotyped, complex, but purposeless motor activity, such as sorting or lining up various objects or repetitive grooming behavior. It responds to reduction in dose of dopaminergic agents or to atypical antipsychotic agents.
D. Dyskinesias and Response Fluctuations
Dyskinesias occur in up to 80% of patients receiving levodopa therapy for more than 10 years. The character of dopa dyskinesias varies between patients but tends to remain constant in individual patients. Choreoathetosis of the face and distal extremities is the most common presentation. The development of dyskinesias is dose related, but there is considerable individual variation in the dose required to produce them. Their pathogenesis is unclear, but they may relate to an unequal distribution of striatal dopamine. Dopaminergic denervation plus chronic pulsatile stimulation of dopamine receptors with levodopa has been associated with development of dyskinesias. A lower incidence of dyskinesias occurs when levodopa is administered continuously (eg, intraduodenally or intrajejunally) and with drug delivery systems that enable a more continuous delivery of dopaminergic medication. Reduction of levodopa dose will alleviate dyskinesias, but motor symptoms of parkinsonism then worsen. Mild dyskinesias require no treatment. Amantadine may help to reduce more troublesome dyskinesias, as may clozapine; a number of other compounds are being studied as possible antidyskinetic agents.
Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake (wearing-off reactions or end-of-dose akinesia). In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. For patients with severe off-periods who are unresponsive to other measures, subcutaneously injected apomorphine may provide temporary benefit but may increase dyskinesias. The on-off phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown.
E. Miscellaneous Adverse Effects