Pathophysiology of Psychosis and Risk Factors

The pathophysiology of psychosis in PD is poorly understood, but dopaminergic and serotonergic mechanisms have been proposed. One theory is that chronic excessive stimulation of dopamine receptors, particularly in the mesolimbic/mesocorti-cal pathways, causes hypersensitization, resulting in psychosis when patients are treated with dopaminergic agents (36). However, exogenous dopamine supplementation by itself is not the only factor in the development of psychosis since all PD medications (anticholinergics, dopaminergics, and amantadine) can induce similar hallucinations despite their different mechanisms of action (25), and PD psychosis was described prior to the use of levodopa (37). Serotonin has been implicated because the atypical antipsychotic drugs are purported to work through their high affinity for 5-HT2 compared to D2 receptors. However, PD patients with psychosis have decreased serotonin content in the brainstem at autopsy (38). Potential explanations for this finding include postsynaptic serotonergic hypersensitivity as a result of decreased central serotonin activity (39) and/or increases in serotonin activity from levodopa administration (40).

The precise anatomic substrate of hallucinations and psychosis is unknown, but may be due in part to visual dysfunction. PD patients who hallucinate perform slightly worse on visual acuity testing (mean visual acuity 20/45) than nonhalluci-nators (20/33) (17) and have greater impairment in color vision and contrast sensitivity (41). Furthermore, visual evoked potentials are abnormal in PD patients with visual hallucinations (42). Other structures in the brain may also be involved. One reported patient experienced formed visual hallucinations after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery only when the stimulators were turned on (43), leading the authors to hypothesize that this resulted from stimulation of limbic fibers near the STN. Finally, a functional MRI study demonstrated greater activation in the frontal lobe in PD patients with chronic visual hallucinations compared to nonhallucinators (44). The exact contribution of these neurotransmitters and structures to the genesis of psychosis is unclear.

The presence of dementia, advancing age, impaired vision, depression, sleep disorders, and longer disease duration have all been associated with the development of drug-induced psychosis (15,45-48). Although psychosis has been reported to occur with all of the antiparkinsonian medications (22-25), the dopamine agonists are more likely to cause psychosis than levodopa (49,50). The duration or dose of antiparkinsonian drug therapy, however, has not been found to be associated with an increased risk for psychosis (45,51,52).

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