Psychosis is a frequent nonmotor complication in Parkinson's disease (PD), characterized by a broad phenomenology and likely due to a variety of intrinsic (i.e., PD-related) and extrinsic factors. Safe and effective therapies are greatly needed as PD psychosis contributes significantly to morbidity, mortality, nursing home placement, and quality of life. Novel research strategies focused on understanding the pharmacology and pathophysiology of PD psychosis, utilizing translational research including animal models, genetics, and neuroimaging, and even looking beyond the dopamine system may further therapeutic advances. This review discusses new research strategies regarding the neurobiology and treatment of PD psychosis and several associated challenges. 1. Introduction Psychosis is a frequent nonmotor complication of Parkinson’s disease (PD) [1–3]. Psychotic symptoms in PD manifest predominantly as hallucinations and delusions, although recently revised criteria for PD psychosis extend the spectrum to include illusions, a false sense of presence, hallucinations, and delusions [4]. These neuropsychiatric phenomena likely stem from a combination of drug-related (i.e., exogenous or extrinsic) factors and PD-related (i.e., endogenous or intrinsic) complications, although the exact pathophysiology of PD psychosis is unknown. Improved treatments for PD psychosis are greatly needed since hallucinations and delusions are important contributors to morbidity, mortality, nursing home placement, and quality of life [5–7]. To date, many clinical research trials for antipsychotic medications in PD have been affected by issues of trial design, medication side effects, and negative outcomes. As such, the goal of optimally designed clinical trials with effective and safe medications presents a challenge. Use of animal models or biomarkers (e.g., genetic or neuroimaging) may provide additional and complementary ways to advance treatments for PD psychosis. Thus, the aim of this review is to discuss new research strategies regarding PD psychosis and their associated challenges. This review will highlight research on nondopaminergic substrates, comorbid neuropsychiatric features often associated with PD psychosis and the potential roles for integrating in vivo neuroimaging, genetic risk factors, and animal models in studying PD psychosis, and lastly discuss challenges of medication trials. Dopaminergic medications have been well recognized to induce psychosis in PD by stimulating or inducing hypersensitivity of mesocorticolimbic dopamine receptors [8–10]. Virtually all
References
[1]
G. Fenelon and G. Alves, “Epidemiology of psychosis in Parkinson's disease,” Journal of the Neurological Sciences, vol. 289, no. 1-2, pp. 12–17, 2010.
[2]
G. Fenelon, F. Mahieux, R. Huon, and M. Ziégler, “Hallucinations in Parkinson's disease. Prevalence, phenomenology and risk factors,” Brain, vol. 123, no. 4, pp. 733–745, 2000.
[3]
J. R. Sanchez-Ramos, R. Ortoll, and G. W. Paulson, “Visual hallucinations associated with Parkinson disease,” Archives of Neurology, vol. 53, no. 12, pp. 1265–1268, 1996.
[4]
B. Ravina, K. Marder, H. H. Fernandez et al., “Diagnostic criteria for psychosis in Parkinson's disease: report of an NINDS, NIMH Work Group,” Movement Disorders, vol. 22, no. 8, pp. 1061–1068, 2007.
[5]
C. G. Goetz and G. T. Stebbins, “Risk factors for nursing home placement in advanced Parkinson's disease,” Neurology, vol. 43, no. 11, pp. 2227–2229, 1993.
[6]
C. G. Goetz and G. T. Stebbins, “Mortality and hallucinations in nursing home patients with advanced Parkinson's disease,” Neurology, vol. 45, no. 4, pp. 669–671, 1995.
[7]
D. Aarsland, J. P. Larsen, E. Tandberg, and K. Laake, “Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study,” Journal of the American Geriatrics Society, vol. 48, no. 8, pp. 938–942, 2000.
[8]
S. Kuzuhara, “Drug-induced psychotic symptoms in Parkinson's disease. Problems, management and dilemma,” Journal of Neurology, vol. 248, supplement 3, pp. III28–III31, 2001.
[9]
E. C. H. Wolters, “Intrinsic and extrinsic psychosis in Parkinson's disease,” Journal of Neurology, Supplement, vol. 248, supplement 3, pp. 22–27, 2001.
[10]
E. C. H. Wolters, “PD-related psychosis: pathophysiology with therapeutical strategies,” Journal of Neural Transmission, Supplement, no. 71, pp. 31–37, 2006.
[11]
R. Holloway, I. Shoulson, K. Kieburtz et al., “Pramipexole vs Levodopa as initial treatment for Parkinson disease: a randomized controlled trial,” Journal of the American Medical Association, vol. 284, no. 15, pp. 1931–1938, 2000.
[12]
K. M. Biglan, R. G. Holloway, M. P. McDermott, and I. H. Richard, “Risk factors for somnolence, edema, and hallucinations in early Parkinson disease,” Neurology, vol. 69, no. 2, pp. 187–195, 2007.
[13]
P. A. LeWitt, K. E. Lyons, and R. Pahwa, “Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study,” Neurology, vol. 68, no. 16, pp. 1262–1267, 2007.
[14]
O. Rascol, D. J. Brooks, A. D. Korczyn, P. P. De Deyn, C. E. Clarke, and A. E. Lang, “A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa,” The New England Journal of Medicine, vol. 342, no. 20, pp. 1484–1491, 2000.
[15]
U. K. Rinne, F. Bracco, C. Chouza et al., “Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial,” Drugs, vol. 55, supplement 1, pp. 23–30, 1998.
[16]
Y. De Smet, M. Ruberg, and M. Serdaru, “Confusion, dementia and anticholinergics in Parkinson's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 45, no. 12, pp. 1161–1164, 1982.
[17]
N. J. Diederich, C. G. Goetz, R. Raman, E. J. Pappert, S. Leurgans, and V. Piery, “Poor visual discrimination and visual hallucinations in Parkinson's disease,” Clinical Neuropharmacology, vol. 21, no. 5, pp. 289–295, 1998.
[18]
N. J. Diederich, C. G. Goetz, and G. T. Stebbins, “Repeated visual hallucinations in Parkinson's disease as disturbed external/internal perceptions: focused review and a new integrative model,” Movement Disorders, vol. 20, no. 2, pp. 130–140, 2005.
[19]
S. Holroyd, L. Currie, and G. F. Wooten, “Prospective study of hallucinations and delusions in Parkinson's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 6, pp. 734–738, 2001.
[20]
S. Holroyd and G. F. Wooten, “Preliminary fMRI evidence of visual system dysfunction in Parkinson's disease patients with visual hallucinations,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 18, no. 3, pp. 402–404, 2006.
[21]
V. Pieri, N. J. Diederich, R. Raman, and C. G. Goetz, “Decreased color discrimination and contrast sensitivity in Parkinson's disease,” Journal of the Neurological Sciences, vol. 172, no. 1, pp. 7–11, 2000.
[22]
G. T. Stebbins, G. G. Goetz, M. C. Carrillo et al., “Altered cortical visual processing in PD with hallucinations: an fMRI study,” Neurology, vol. 63, no. 8, pp. 1409–1416, 2004.
[23]
J. Barnes and L. Boubert, “Executive functions are impaired in patients with Parkinson's disease with visual hallucinations,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 2, pp. 190–192, 2008.
[24]
A. M. Meppelink, J. Koerts, M. Borg, K. L. Leenders, and T. van Laar, “Visual object recognition and attention in Parkinson's disease patients with visual hallucinations,” Movement Disorders, vol. 23, no. 13, pp. 1906–1912, 2008.
[25]
B. Ramírez-Ruiz, C. Junqué, M. J. Martí, F. Valldeoriola, and E. Toloso, “Neuropsychological deficits in Parkinson's disease patients with visual hallucinations,” Movement Disorders, vol. 21, no. 9, pp. 1483–1487, 2006.
[26]
B. Ramirez-Ruiz, C. Junque, M. J. Marti, F. Valldeoriola, and E. Tolosa, “Cognitive changes in Parkinson's disease patients with visual hallucinations,” Dementia and Geriatric Cognitive Disorders, vol. 23, no. 5, pp. 281–288, 2007.
[27]
I. Arnulf, A. M. Bonnet, P. Damier et al., “Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis,” Neurology, vol. 55, no. 2, pp. 281–288, 2000.
[28]
I. Arnulf, S. Leu, and D. Oudiette, “Abnormal sleep and sleepiness in Parkinson's disease,” Current Opinion in Neurology, vol. 21, no. 4, pp. 472–477, 2008.
[29]
C. L. Comella, “Sleep disorders in Parkinson's disease: an overview,” Movement Disorders, vol. 22, no. 17, pp. S367–S373, 2007.
[30]
R. B. Postuma, J. F. Gagnon, M. Vendette, K. Charland, and J. Montplaisir, “Manifestations of Parkinson disease differ in association with REM sleep behavior disorder,” Movement Disorders, vol. 23, no. 12, pp. 1665–1672, 2008.
[31]
E. Sinforiani, C. Pacchetti, R. Zangaglia, C. Pasotti, R. Manni, and G. Nappi, “REM behavior disorder, hallucinations and cognitive impairment in Parkinson's disease: a two-year follow up,” Movement Disorders, vol. 23, no. 10, pp. 1441–1445, 2008.
[32]
E. Sinforiani, R. Zangaglia, R. Manni et al., “REM sleep behavior disorder, hallucinations, and cognitive impairment in Parkinson's disease,” Movement Disorders, vol. 21, no. 4, pp. 462–466, 2006.
[33]
D. L. Whitehead, A. D. M. Davies, J. R. Playfer, and C. J. Turnbull, “Circadian rest-activity rhythm is altered in Parkinson's disease patients with hallucinations,” Movement Disorders, vol. 23, no. 8, pp. 1137–1145, 2008.
[34]
H. Boecker, A. O. Ceballos-Baumann, D. Volk, B. Conrad, H. Forstl, and P. Haussermann, “Metabolic alterations in patients with Parkinson disease and visual hallucinations,” Archives of Neurology, vol. 64, no. 7, pp. 984–988, 2007.
[35]
N. Ibarretxe-Bilbao, B. Ramírez-Ruiz, E. Tolosa et al., “Hippocampal head atrophy predominance in Parkinson's disease with hallucinations and with dementia,” Journal of Neurology, vol. 255, no. 9, pp. 1324–1331, 2008.
[36]
H. Kataoka, Y. Furiya, M. Morikawa, S. Ueno, and M. Inoue, “Increased temporal blood flow associated with visual hallucinations in Parkinson's disease with dementia,” Movement Disorders, vol. 23, no. 3, pp. 464–465, 2008.
[37]
H. Matsui, K. Nishinaka, T. Miyoshi et al., “Thalamic hyperperfusion in verbal hallucination of Parkinsonian patients,” Internal Medicine, vol. 46, no. 21, pp. 1765–1769, 2007.
[38]
H. Matsui, K. Nishinaka, M. Oda et al., “Hypoperfusion of the visual pathway in parkinsonian patients with visual hallucinations,” Movement Disorders, vol. 21, no. 12, pp. 2140–2144, 2006.
[39]
B. Ramírez-Ruiz, M. J. Martí, E. Tolosa et al., “Brain response to complex visual stimuli in Parkinson's patients with hallucinations: a functional magnetic resonance imaging study,” Movement Disorders, vol. 23, no. 16, pp. 2335–2343, 2008.
[40]
B. Ramírez-Ruiz, M. J. Martí, E. Tolosa et al., “Cerebral atrophy in Parkinson's disease patients with visual hallucinations,” European Journal of Neurology, vol. 14, no. 7, pp. 750–756, 2007.
[41]
E. K. Perry, M. Curtis, and D. J. Dick, “Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 48, no. 5, pp. 413–421, 1985.
[42]
R. M. Zweig, W. R. Jankel, J. C. Hedreen, R. Mayeux, and D. L. Price, “The pedunculopontine nucleus in Parkinson's disease,” Annals of Neurology, vol. 26, no. 1, pp. 41–46, 1989.
[43]
E. K. Perry and R. H. Perry, “Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness,” Brain and Cognition, vol. 28, no. 3, pp. 240–258, 1995.
[44]
D. Aarsland, K. Br?nnick, U. Ehrt et al., “Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 1, pp. 36–42, 2007.
[45]
D. Aarsland, K. Andersen, J. P. Larsen, A. Lolk, and P. Kragh-S?rensen, “Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study,” Archives of Neurology, vol. 60, no. 3, pp. 387–392, 2003.
[46]
D. Aarsland, K. Andersen, J. P. Larsen et al., “The rate of cognitive decline in Parkinson disease,” Archives of Neurology, vol. 61, no. 12, pp. 1906–1911, 2004.
[47]
M. Emre, D. Aarsland, A. Albanese et al., “Rivastigmine for dementia associated with Parkinson's disease,” The New England Journal of Medicine, vol. 351, no. 24, pp. 2509–2518, 2004.
[48]
D. Burn, M. Emre, I. McKeith et al., “Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease,” Movement Disorders, vol. 21, no. 11, pp. 1899–1907, 2006.
[49]
C. G. Goetz, J. Wuu, L. M. Curgian, and S. Leurgans, “Hallucinations and sleep disorders in PD: six-year prospective longitudinal study,” Neurology, vol. 64, no. 1, pp. 81–86, 2005.
[50]
E. B. Forsaa, J. P. Larsen, T. Wentzel-Larsen et al., “A 12-year population-based study of psychosis in Parkinson disease,” Archives of Neurology, vol. 67, no. 8, pp. 996–1001, 2010.
[51]
C. L. Comella, C. M. Tanner, and R. K. Ristanovic, “Polysomnographic sleep measures in Parkinson's disease patients with treatment-induced hallucinations,” Annals of Neurology, vol. 34, no. 5, pp. 710–714, 1993.
[52]
R. Manni, C. Pacchetti, M. Terzaghi, I. Sartori, F. Mancini, and G. Nappi, “Hallucinations and sleep-wake cycle in PD: a 24-hour continuous polysomnographic study,” Neurology, vol. 59, no. 12, pp. 1979–1981, 2002.
[53]
T. Nomura, Y. Inoue, H. Mitani, R. Kawahara, M. Miyake, and K. Nakashima, “Visual hallucinations as REM sleep behavior disorders in patients with Parkinson's disease,” Movement Disorders, vol. 18, no. 7, pp. 812–817, 2003.
[54]
C. B. Saper, T. C. Chou, and T. E. Scammell, “The sleep switch: hypothalamic control of sleep and wakefulness,” Trends in Neurosciences, vol. 24, no. 12, pp. 726–731, 2001.
[55]
H. H. Fernandez, M. S. Okun, R. L. Rodriguez et al., “Quetiapine improves visual hallucinations in parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study,” International Journal of Neuroscience, vol. 119, no. 12, pp. 2196–2205, 2009.
[56]
W. Birkmayer and P. Riederer, “Responsibility of extrastriatal areas for the appearance of psychotic symptoms. (Clinical and biochemical human post mortem findings),” Journal of Neural Transmission, vol. 37, no. 2, pp. 175–182, 1975.
[57]
B. Ballanger, A. P. Strafella, T. Van Eimeren et al., “Serotonin 2A receptors and visual hallucinations in Parkinson disease,” Archives of Neurology, vol. 67, no. 4, pp. 416–421, 2010.
[58]
P. Huot, T. H. Johnston, T. Darr et al., “Increased 5-HT2A receptors in the temporal cortex of Parkinsonian patients with visual hallucinations,” Movement Disorders, vol. 25, no. 10, pp. 1399–1408, 2010.
[59]
G. Meco and S. Bernardi, “Antidepressant use in treatment of psychosis with comorbid depression in Parkinson's disease,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 31, no. 1, pp. 311–313, 2007.
[60]
V. Voon, S. Fox, T. R. Butler, and A. E. Lang, “Antidepressants and psychosis in Parkinson disease: a case series,” International Journal of Geriatric Psychiatry, vol. 22, no. 6, pp. 601–604, 2007.
[61]
V. Voon and A. E. Lang, “Antidepressants in the treatment of psychosis with comorbid depression in Parkinson disease,” Clinical Neuropharmacology, vol. 27, no. 2, pp. 90–92, 2004.
[62]
C. G. Goetz, C. M. Tanner, and H. L. Klawans, “Bupropion in Parkinson's disease,” Neurology, vol. 34, no. 8, pp. 1092–1094, 1984.
[63]
E. C. Lauterbach, “Dopaminergic hallucinosis with fluoxetine in Parkinson's disease,” American Journal of Psychiatry, vol. 150, no. 11, p. 1750, 1993.
[64]
C. Normann, B. Hesslinger, S. Frauenknecht, M. Berger, and J. Walden, “Psychosis during chronic levodopa therapy triggered by the new antidepressive drug mirtazapine,” Pharmacopsychiatry, vol. 30, no. 6, pp. 263–265, 1997.
[65]
C. Wlodarek, J. Wuu, and C. G. Goetz, “The effect of SSRI's on hallucinations in Parkinson's disease patients with depression,” Annals of Neurology, vol. 60, no. S3, p. S82, 2006.
[66]
L. Marsh, J. R. Williams, M. Rocco, S. Grill, C. Munro, and T. M. Dawson, “Psychiatric comorbidities in patients with Parkinson disease and psychosis,” Neurology, vol. 63, no. 2, pp. 293–300, 2004.
[67]
N. Ibarretxe-Bilbao, B. Ramirez-Ruiz, C. Junque et al., “Differential progression of brain atrophy in Parkinson's disease with and without visual hallucinations,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 6, pp. 650–657, 2010.
[68]
B. Ramírez-Ruiz, M. J. Martí, E. Tolosa et al., “Brain response to complex visual stimuli in Parkinson's patients with hallucinations: a functional magnetic resonance imaging study,” Movement Disorders, vol. 23, no. 16, pp. 2335–2343, 2008.
[69]
A. M. Meppelink, B. M. De Jong, R. Renken, K. L. Leenders, F. W. Cornelissen, and T. Van Laar, “Impaired visual processing preceding image recognition in Parkinson's disease patients with visual hallucinations,” Brain, vol. 132, no. 11, pp. 2980–2993, 2009.
[70]
K. Okada, N. Suyama, H. Oguro, S. Yamaguchi, and S. Kobayashi, “Medication-induced hallucination and cerebral blood flow in Parkinson's disease,” Journal of Neurology, vol. 246, no. 5, pp. 365–368, 1999.
[71]
N. Oishi, F. Udaka, M. Kameyama, N. Sawamoto, K. Hashikawa, and H. Fukuyama, “Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations,” Neurology, vol. 65, no. 11, pp. 1708–1715, 2005.
[72]
A. Nagano-Saito, Y. Washimi, Y. Arahata et al., “Visual hallucination in Parkinson's disease with FDG PET,” Movement Disorders, vol. 19, no. 7, pp. 801–806, 2004.
[73]
M. E. L. Arbouw, J. P. P. van Vugt, T. C. G. Egberts, and H. J. Guchelaar, “Pharmacogenetics of antiparkinsonian drug treatment: a systematic review,” Pharmacogenomics, vol. 8, no. 2, pp. 159–176, 2007.
[74]
L. Skipper, J. J. Liu, and E. K. Tan, “Polymorphisms in candidate genes: implications for the current treatment of Parkinson's disease,” Expert Opinion on Pharmacotherapy, vol. 7, no. 7, pp. 849–855, 2006.
[75]
A. J. Makoff, J. M. Graham, M. J. Arranz et al., “Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson's disease,” Pharmacogenetics, vol. 10, no. 1, pp. 43–48, 2000.
[76]
C. G. Goetz, P. F. Burke, S. Leurgans et al., “Genetic variation analysis in Parkinson disease patients with and without hallucinations: case-control study,” Archives of Neurology, vol. 58, no. 2, pp. 209–213, 2001.
[77]
J. Wang, C. Zhao, B. Chen, and Z. L. Liu, “Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease,” Neuroscience Letters, vol. 355, no. 3, pp. 193–196, 2004.
[78]
R. L. Oliveri, G. Annesi, M. Zappia et al., “Dopamine D receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD,” Neurology, vol. 53, no. 7, pp. 1425–1430, 1999.
[79]
J. Wang, Z. L. Liu, and B. Chen, “Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD,” Neurology, vol. 56, no. 12, pp. 1757–1759, 2001.
[80]
R. Kaiser, A. Hofer, A. Grapengiesser et al., “L-Dopa-induced adverse effects in PD and dopamine transporter gene polymorphism,” Neurology, vol. 60, no. 11, pp. 1750–1755, 2003.
[81]
J. G. Goldman, C. G. Goetz, E. Berry-Kravis, et al., “Genetic polymorphisms of the dopamine transporter gene and hallucinations in Parkinson's disease,” Movement Disorders, vol. 19, no. 9, p. S356, 2004.
[82]
K. P. Lesch, D. Bengel, A. Heils et al., “Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region,” Science, vol. 274, no. 5292, pp. 1527–1531, 1996.
[83]
A. D. Ogilvie, S. Battersby, V. J. Bubb et al., “Polymorphism in serotonin transporter gene associated with susceptibility to major depression,” The Lancet, vol. 347, no. 9003, pp. 731–733, 1996.
[84]
K. P. Lesch, U. Balling, J. Gross et al., “Organization of the human serotonin transporter gene,” Journal of Neural Transmission, vol. 95, no. 2, pp. 157–162, 1994.
[85]
M. A. Menza, B. Palermo, R. DiPaola, J. I. Sage, and M. H. Ricketts, “Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter,” Journal of Geriatric Psychiatry and Neurology, vol. 12, no. 2, pp. 49–52, 1999.
[86]
S. J. McCann, M. E. McManus, A. G. Johnson, G. D. Mellick, D. G. Le Couteur, and S. M. Pond, “The serotonin transporter gene and Parkinson's disease,” European Neurology, vol. 44, no. 2, pp. 108–111, 2000.
[87]
J. G. Goldman, C. G. Goetz, E. Berry-Kravis, et al., “Serotonin transporter gene polymorphisms and hallucinations in Parkinson's disease,” Annals of Neurology, vol. 56, no. S8, p. S26, 2004.
[88]
L. Kiferle, R. Ceravolo, L. Petrozzi et al., “Visual hallucinations in Parkinson's disease are not influenced by polymorphisms of serotonin 5-HT2A receptor and transporter genes,” Neuroscience Letters, vol. 422, no. 3, pp. 228–231, 2007.
[89]
J. Wei and G. P. Hemmings, “The CCK-A receptor gene possibly associated with auditory hallucinations in schizophrenia,” European Psychiatry, vol. 14, no. 2, pp. 67–70, 1999.
[90]
J. N. Crawley, “Cholecystokinin—dopamine interactions,” Trends in Pharmacological Sciences, vol. 12, no. 6, pp. 232–236, 1991.
[91]
C. Fujii, S. Harada, N. Ohkoshi et al., “Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease,” Clinical Genetics, vol. 56, no. 5, pp. 394–399, 1999.
[92]
T. V. O. Hansen, “Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways,” Peptides, vol. 22, no. 8, pp. 1201–1211, 2001.
[93]
J. Wang, Y. M. Si, Z. L. Liu, and L. Yu, “Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease,” Pharmacogenetics, vol. 13, no. 6, pp. 365–369, 2003.
[94]
J. G. Goldman, C. G. Goetz, E. Berry-Kravis, S. Leurgans, and L. Zhou, “Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system,” Archives of Neurology, vol. 61, no. 8, pp. 1280–1284, 2004.
[95]
R. De La Fuente-Fernández, M. A. Nú?ez, and E. López, “The apolipoprotein E ε4 allele increases the risk of drug-induced hallucinations in Parkinson's disease,” Clinical Neuropharmacology, vol. 22, no. 4, pp. 226–230, 1999.
[96]
R. Camicioli, A. Rajput, M. Rajput et al., “Apolipoprotein E ε4 and catechol-O-methyltransferase alleles in autopsy-proven Parkinson's disease: relationship to dementia and hallucinations,” Movement Disorders, vol. 20, no. 8, pp. 989–994, 2005.
[97]
R. E. Featherstone, S. Kapur, and P. J. Fletcher, “The amphetamine-induced sensitized state as a model of schizophrenia,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 31, no. 8, pp. 1556–1571, 2007.
[98]
F. Owen, H. F. Baker, and R. M. Ridley, “Effect of chronic amphetamine administration on dopaminergic systems in the vervet brain: relationship to findings in the brains of schizophrenics,” Biochemical Society Transactions, vol. 11, no. 1, pp. 68–69, 1983.
[99]
R. M. Ridley, H. F. Baker, and F. Owen, “Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey,” Psychopharmacology, vol. 78, no. 3, pp. 245–251, 1982.
[100]
S. H. Fox, N. P. Visanji, T. H. Johnston, J. Gomez-Ramirez, V. Voon, and J. M. Brotchie, “Dopamine receptor agonists and levodopa and inducing psychosis-like behavior in the MPTP primate model of Parkinson disease,” Archives of Neurology, vol. 63, no. 9, pp. 1343–1344, 2006.
[101]
N. P. Visanji, J. Gomez-Ramirez, T. H. Johnston et al., “Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease,” Movement Disorders, vol. 21, no. 11, pp. 1879–1891, 2006.
[102]
J. Song, D. Hanniford, C. Doucette et al., “Development of homogenous high-affinity agonist binding assays for 5-HT2 receptor subtypes,” Assay and Drug Development Technologies, vol. 3, no. 6, pp. 649–659, 2005.
[103]
K. E. Vanover, A. J. Betz, S. M. Weber et al., “A 5-HT receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model,” Pharmacology Biochemistry and Behavior, vol. 90, no. 4, pp. 540–544, 2008.
[104]
S. A. Factor and J. H. Friedman, “The emerging role of clozapine in the treatment of improvement disorders,” Movement Disorders, vol. 12, no. 4, pp. 483–496, 1997.
[105]
J. H. Friedman, “Parkinson's disease psychosis 2010: a review article,” Parkinsonism and Related Disorders, vol. 16, no. 9, pp. 553–560, 2010.
[106]
H. Y. Meltzer, J. I. Koenig, J. F. Nash, and G. A. Gudelsky, “Melperone and clozapine: neuroendocrine effects of atypical neuroleptic drugs,” Acta Psychiatrica Scandinavica, Supplement, vol. 80, no. 352, pp. 24–29, 1989.
[107]
H. Y. Meltzer, S. Matsubara, and J.-C. Lee, “The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs,” Psychopharmacology Bulletin, vol. 25, no. 3, pp. 390–392, 1989.
[108]
L. Barbato, A. Monge, F. Stocchi, and G. Nordera, “Melperone in the treatment of iatrogenic psychosis in Parkinson's disease,” Functional Neurology, vol. 11, no. 4, pp. 201–207, 1996.
[109]
A. Abbas and B. L. Roth, “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders,” Expert Opinion on Pharmacotherapy, vol. 9, no. 18, pp. 3251–3259, 2008.
[110]
C. Roberts, “ACP-103, a 5-HT receptor inverse agonist,” Current Opinion in Investigational Drugs, vol. 7, no. 7, pp. 653–660, 2006.
[111]
H. Y. Meltzer, R. Mills, S. Revell et al., “Pimavanserin, a serotonin 2A receptor inverse agonist, for the treatment of Parkinson's disease psychosis,” Neuropsychopharmacology, vol. 35, no. 4, pp. 881–892, 2010.
[112]
R. B. Friedman, J. H. Mills, R. Mills, et al., “A multicenter, placebo controlled, double blind trial to examine the safety and efficacy of pimavanserin in the treatment of psychosis in Parkinson's disease,” Neurology, vol. 74, no. S2, p. A299, 2010.
[113]
B. R. Teegarden, H. Al Shamma, and Y. Xiong, “5-HT2A inverse-agonists for the treatment of insomnia,” Current Topics in Medicinal Chemistry, vol. 8, no. 11, pp. 969–976, 2008.
[114]
J. H. Friedman, “Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. The Parkinson Study Group,” The New England Journal of Medicine, vol. 340, no. 10, pp. 757–763, 1999.
[115]
L. Morgante, A. Epifanio, E. Spina et al., “Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's disease,” Neurological Sciences, vol. 23, supplement 2, pp. S89–S90, 2002.
[116]
A. Breier, V. K. Sutton, P. D. Feldman et al., “Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease,” Biological Psychiatry, vol. 52, no. 5, pp. 438–445, 2002.
[117]
W. G. Ondo, J. K. Levy, K. D. Vuong, C. Hunter, and J. Jankovic, “Olanzapine treatment for dopaminergic-induced hallucinations,” Movement Disorders, vol. 17, no. 5, pp. 1031–1035, 2002.
[118]
J. M. Miyasaki, K. Shannon, V. Voon et al., “Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology,” Neurology, vol. 66, no. 7, pp. 996–1002, 2006.
[119]
R. Kurlan, J. Cummings, R. Raman, and L. Thal, “Quetiapine for agitation or psychosis in patients with dementia and parkinsonism,” Neurology, vol. 68, no. 17, pp. 1356–1363, 2007.
[120]
W. G. Ondo, R. Tintner, K. D. Voung, D. Lai, and G. Ringholz, “Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease,” Movement Disorders, vol. 20, no. 8, pp. 958–963, 2005.