The onset of psychiatric symptoms coincident with the use of l-dopa or dopamine agonists may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly. Confusion and outright psychosis (hallucinations and delusions) are seen in advanced cases of Parkinson disease when high doses of l-dopa are required and the disease has been present for many years. This may first be treated by reducing the dose of the drug. If this is not tolerated, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine may be given in low doses. The side effects of these drugs include sleepiness, orthostatic hypotension, and sialorrhea. As noted above, clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease, but its hematologic risks have led to limited use. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The antiepileptic drug, valproate is also said to be useful in this circumstance, but it has not been as effective as clozapine and related drugs. Despite its lesser tendency to produce rigidity, olanzapine, and probably the other similar agents, in high doses may slightly worsen motor disability.
Depression, although frequent, is only occasionally a serious problem, even to the point of suicide. Delusional thinking may also occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one is faced with instituting an antidepressant regimen or perhaps using one of the newer classes of antipsychotic medications that have the least extrapyramidal side effects (see in the following text). While the selective serotonin reuptake inhibitors have been useful in cases of apathetic depression, they may cause slight worsening of parkinsonian symptoms. Trazodone has been helpful in treating depression and insomnia, the latter also being a major problem in some patients. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness. Other curious effects of excessive drive from l-dopa and dopamine agonists have been pathologic gambling as mentioned earlier (the same has been seen in treatment of restless legs syndrome) and odd behaviors such as cross-dressing (Quinn et al, 1983).
Anticholinergic agents or l-dopa should not generally be discontinued abruptly in advanced Parkinson disease. If abruptly discontinued, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal. Reducing the medication dose over a week or so is usually adequate.
With progressive loss of nigral cells, there is an increasing inability to store l-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to l-dopa that 50 to 100 mg will precipitate dyskinesias; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and the on–off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the morning and much less well in the afternoon, or vice versa. In such cases, and for end-of-dose and on–off phenomena, one may titrate the dose of l-dopa and use more frequent dosing during the 24-h day; combining it with a dopamine agonist or a long-acting preparation may be helpful. Sometimes temporarily withdrawing l-dopa and at the same time substituting other medications may reduce the on–off phenomenon.