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Mechanism of action of pimavanserin in Parkinson’s disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors

Published online by Cambridge University Press:  09 August 2016

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Abstract

Pimavanserin, a novel agent approved for the treatment of Parkinson’s disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors.

Type
Brainstorms
Copyright
© Cambridge University Press 2016 

Take-Home Points

  • 1. Pimavanserin is a selective 5HT2A/5HT2C receptor-acting agent and the only approved treatment for Parkinson’s disease psychosis.

  • 2. Pimavanserin is the first example of a drug with antipsychotic actions that does not block dopamine D2 receptors.

  • 3. The antipsychotic actions of pimavanserin, particularly against visual hallucinations in Parkinson’s disease psychosis, do not come at the expense of worsening motor symptoms in Parkinson’s disease.

Introduction

Psychosis, defined as hallucinations and delusions, is present in up to half of patients with Parkinson’s disease,Reference Cummings 1 Reference Goldman, Vaughan and Goetz 4 but there is debate about its cause. In some Parkinson’s disease patients, Parkinson’s disease psychosis (PDP) appears even before motor symptoms occur or before any treatment is given, and is thus a core non-motor feature of their Parkinson’s disease;Reference Cummings 1 Reference Paponabarrage, Martinez-Horta and Fernández de Bobadilla 5 in other patients with Parkinson’s disease, PDP develops concomitantly with dementia, both the Alzheimer type and the Lewy body type, in which Lewy bodies of alpha synuclein accumulate not only in the substantia nigra, first to cause motor symptoms, but also in the cortex, later to cause dementia;Reference Cummings 1 Reference Paponabarrage, Martinez-Horta and Fernández de Bobadilla 5 finally, PDP in yet other patients with Parkinson’s disease seems to be caused or worsened by treatment with dopaminergic agents and improved by dose reduction of dopaminergic therapies.Reference Cummings 1 Reference Goldman, Vaughan and Goetz 4 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 Whatever the cause of PDP, it is clear that its onset is not good news, since it is associated with dementiaReference Cummings 1 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 and predicts repeated hospitalizations,Reference Klein, Prokhorov, Miniovitz, Dobronevsky and Rabey 9 nursing home placement,Reference Goetz and Stebbins 10 , Reference Aarsland, Larsen, Tandberg and Laake 11 and death.Reference Goetz and Stebbins 12 , Reference Forsaa, Larsen, Wentzel-Larsen and Alves 13 Furthermore, the only previously available treatment for PDP, antipsychotics, can worsen motor symptoms and increase mortality in Parkinson’s disease patients with dementia, many of whom have PDP.Reference Chang and Fox 2 Reference Goldman, Vaughan and Goetz 4 , Reference Schneider, Dagerman and Insel 14 , Reference Ballard, Isaacson and Mills 15 Thus, there is urgent need for a safe and effective treatment for PDP.

From a pharmacologic perspective, PDP likely represents an imbalance between dopamine and serotonin systems in the brain.Reference Chang and Fox 2 Reference Goldman, Vaughan and Goetz 4 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 , Reference Birkmayer and Birkmayer 16 Reference Birkmayer, Danielczyk, Neumayer and Riederer 31 Treatment of PDP, prior to the approval of pimavanserin, consisted of either lowering the doses of dopaminergic antiparkinsonian agents or adding antipsychotic agents, although the efficacy of antipsychotics for PDP has been poorly documented and is often associated with worsening of motor symptoms of Parkinson’s disease.Reference Chang and Fox 2 Reference Goldman, Vaughan and Goetz 4 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 , Reference Zahodne and Fernandez 32 , Reference Desmarais, Massoud, Filion, Nguyen and Bajsarowicz 33 Originally, the notion was that antipsychotics such as quetiapine or clozapine worked in PDP by blocking D2 dopamine receptors,Reference Chang and Fox 2 Reference Goldman, Vaughan and Goetz 4 , Reference Zahodne and Fernandez 32 , Reference Desmarais, Massoud, Filion, Nguyen and Bajsarowicz 33 just as these drugs are thought to work in schizophrenia.Reference Stahl 34 However, a novel line of investigation now suggests that it is actually the potent serotonin 5HT2A antagonist properties of quetiapine and clozapine,Reference Stahl 34 , Reference Hubbard, Hacksell and McFarland 35 not their weak D2 antagonist properties, that cause the apparent efficacy seen in Parkinson’s disease. That is, pimavanserin—which lacks any potent D2 antagonist actionsReference Vanover, Weiner and Makhay 36 —has now been proven effective in PDP.Reference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40

Pharmacologic Mechanism of Action of Pimavanserin

Pimavanserin has relatively selective pharmacologic actions, namely, potent interactions at serotonin 5HT2A receptors and around 40-fold less potent activity at 5HT2C receptors (Figure 1).Reference Vanover, Weiner and Makhay 36 It is not clear whether pimavanserin acts only via 5HT2A receptors or via 5HT2C receptors as well, but the doses of pimavanserin required to treat PDPReference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40 suggest that the 5HT2C receptor actions of pimavanserin are indeed relevant to its therapeutic effects in PDP. That is, doses that essentially saturate the 5HT2A receptorReference Vanover, Robbins-Weilert and Wilbraham 41 , Reference Nordstrom, Mansson and Jovanovic 42 are not effective in PDP.Reference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40 However, twice this dose is effective,Reference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40 and this higher dose—the one that is approved for treatment of PDP by the FDA—not only saturates 5HT2A receptors,Reference Nordstrom, Mansson and Jovanovic 42 but also recruits substantial if lesser degrees of occupancy of 5HT2C receptors.Reference Vanover, Weiner and Makhay 36 This notion of dual activity at both 5HT2A and 5HT2C receptors for therapeutic efficacy of pimavanserin in PDP is consistent with animal studies of PDP, where the actions of pimavanserin on dopamine release are demonstrated at doses that engage both receptors as well.Reference Li, Ichikawa, Huang, Prus, Dai and Meltzer 43

Figure 1 Mechanism of action of pimavanserin. Shown here are the binding properties of pimavanserin, namely potent antagonist actions at serotonin 5HT2A receptors, sometimes called inverse agonist actions, and less potent antagonist/inverse agonist actions at 5HT2C receptors. Note that there is no notable binding to D2 dopamine receptors or any other neurotransmitter receptors.

Another unresolved issue regarding the actions of pimavanserin is whether it acts as a more traditional antagonist at 5HT2A/2C receptors, or as a so-called inverse agonist.Reference Stahl 34 , Reference Vanover, Weiner and Makhay 36 , Reference Kenakin 44 , Reference Brink, Harvey, Bodenstein, Venter and Oliver 45 The vast majority of drugs used in psychiatry are antagonists, ie, they block something. Usually they block the effects of an endogenous neurotransmitter, such as dopamine as in the case of treating schizophrenia. Drugs that have the opposite effects of agonists are inverse agonists. For example, from a behavioral point of view, a benzodiazepine agonist reduces anxiety, and a benzodiazepine inverse agonist causes anxiety. From a pharmacologic point of view, antagonists block the actions of agonists at their receptors, but they do so “silently,” that is, without changing any intrinsic activity of that receptor from what that receptor is expressing in the absence of its agonist. On the other hand, an inverse agonist not only blocks the actions of agonists at the receptor the same as an antagonist, but also decreases the intrinsic activity that receptor has in the absence of its agonist. The point of differentiation pharmacologically is that inverse agonists reduce baseline (constitutive) activity at 5HT2A receptors in the absence of serotonin, whereas antagonists do not, ie, they are “silent.”Reference Stahl 34 , Reference Kenakin 44 , Reference Brink, Harvey, Bodenstein, Venter and Oliver 45

From a clinical point of view, the differentiation of an antagonist from an inverse agonist at 5HT2A receptors may be a distinction without a difference. Indeed, the same assay systems that suggest pimavanserin is an inverse agonistReference Vanover, Weiner and Makhay 36 also show that all the other atypical antipsychotics that interact at 5HT2A receptors are also inverse agonists.Reference Weiner, Burstein and Nash 46 Atypical antipsychotics have been traditionally called 5HT2A antagonists, not inverse agonists.Reference Stahl 34 The clinical relevance of this all depends upon whether there is any baseline intrinsic activity of 5HT2A receptors in the living human brain in the absence of serotonin, and we do not have any convincing evidence of that. Thus, there is not yet any known clinically meaningful differentiation between inverse agonism and antagonism for pimavanserin and atypical antipsychotics in PDP, so it may be useful to continue to refer to them simply as antagonists.

Therapeutic Mechanism of Pimavanserin in PDP

Why does blocking 5HT2A/5HT2C receptors in PDP have antipsychotic efficacy without worsening motor symptoms? Although all traditional antipsychotics block D2 receptorsReference Stahl 34 and all atypical antipsychotics block both D2 and 5HT2A receptors,Reference Stahl 34 pimavanserin is the first 5HT2A/2C antagonist lacking D2 antagonist propertiesReference Weiner, Burstein and Nash 46 that has been proven effective in psychosis, specifically PDP.Reference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40 The antipsychotic efficacy of pimavanserin was at first surprising because longstanding dogma about the pharmacology of psychosis assumed it was due to excessive dopamine activity, and the only way to treat psychosis was therefore to reduce dopamine activity. In PDP, that meant the early interventions were either to reduce dopaminergic therapy or to block D2 receptors with the addition of an antipsychotic; however, these treatments both have limited efficacy and also the propensity to make motor symptoms worse.Reference Chang and Fox 2 Reference Goldman, Vaughan and Goetz 4 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 , Reference Zahodne and Fernandez 32 , Reference Desmarais, Massoud, Filion, Nguyen and Bajsarowicz 33 This put both PDP patients and their clinicians between a rock and a hard place when trying to balance simultaneously the treatment of both PDP and motor symptoms of Parkinson’s disease.

Pharmacologists working within the traditional antipsychotic paradigm have long considered the 5HT2A antagonist actions of atypical antipsychotic agents to be responsible for reducing the incidence of drug-induced parkinsonism while simultaneously blocking D2 receptors,Reference Stahl 34 but the evidence that 5HT2A receptors mediate antipsychotic actions was sparse.Reference Stahl 34 , Reference Laoutidis and Luckhaus 47 Other selective 5HT2A antagonists were not convincing antipsychotics as monotherapies, although early preclinical and clinical studies of pimavanserin suggested that it could enhance the antipsychotic activity of risperidone.Reference Gardell, Vanover and Pounds 48 , Reference Meltzer, Elkis and Vanover 49 Thus, it was a bit of a surprise that pimavanserin monotherapy, with its 5HT2A/2C antagonist properties, showed antipsychotic efficacy in PDPReference Cummings, Isaacson and Mills 37 Reference Meltzer, Mills and Revell 40 without blocking D2 receptors.Reference Weiner, Burstein and Nash 46

So, how does the selective 5HT2A/2C antagonism without D2 antagonism of pimavanserin exert its antipsychotic effects in PDP without worsening motor symptoms? It seems the answer to this may be that pimavanserin corrects the theoretical serotonin dopamine imbalance in PDP.Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 , Reference Birkmayer and Birkmayer 16 Reference Birkmayer, Danielczyk, Neumayer and Riederer 31 That is, the various causes of PDP are all hypothesized to act by the same ultimate common pharmacologic pathway, namely to cause an imbalance between serotonin and dopamine. The dopamine deficiencies of Parkinson’s disease are well known and are obviously linked to motor symptoms.Reference Cummings 1 Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 , Reference Ravina, Marek and Eberly 17 , Reference Kordower, Olanaw and Dodiya 18 Less well appreciated is that both serotonin and dopamine neurons degenerate in Parkinson’s disease.Reference Birkmayer and Birkmayer 16 , Reference Huot and Fox 20 Reference Fox, Chuang and Brotchie 22 Although degeneration of dopamine neurons in the substantia nigra is linked to motor symptoms in Parkinson’s disease,Reference Cummings 1 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 6 Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 , Reference Ravina, Marek and Eberly 17 , Reference Kordower, Olanaw and Dodiya 18 loss of serotonin neurons is not.Reference Birkmayer and Birkmayer 16 , Reference Huot and Fox 20 Reference Fox, Chuang and Brotchie 22 Instead, loss of serotonin neurons is accompanied by a presumably compensatory upregulation of post synaptic 5HT2A receptors in the cerebral cortex, setting off an imbalance in the action of serotonin at these receptors.Reference Huot, Hohnston and Darr 23 Reference Albin, Koeppe, Bohnen, Wernette, Kilbourn and Frey 27 That is, excessive stimulation of these receptors is thought to result in psychotic symptoms, especially visual hallucinations, which are the hallmark of PDP.Reference Huot, Hohnston and Darr 23 Reference Birkmayer, Danielczyk, Neumayer and Riederer 31 , Reference Sadzot, Baraban and Glennon 50 Indeed, hallucinogenic drugs cause striking visual hallucinations by stimulating these very same 5HT2A receptors.Reference Sadzot, Baraban and Glennon 50 , Reference McClue, Brazell and Stahl 51 Thus, there is robust pharmacologic rationale to explain why blocking hypothetically overstimulated 5HT2A receptors in PDP would reduce the hypothetical serotonergic imbalance, and thereby stop psychotic symptoms.Reference Huot, Hohnston and Darr 23 Reference Birkmayer, Danielczyk, Neumayer and Riederer 31 , Reference Sadzot, Baraban and Glennon 50 , Reference McClue, Brazell and Stahl 51 Also, 5HT2A receptors in the cortex regulate the downstream release of dopamine,Reference Stahl 34 which has been hypothesized to have undergone a dorsal-to-ventral shift in the striatum in PDP.Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 Blocking these receptors could theoretically restore the correct balance by partially reversing this shift.Reference Joutsa, Johansson, Seppänen, Nopenen and Kaasinen 8 , Reference Huot, Hohnston and Darr 23 Reference Birkmayer, Danielczyk, Neumayer and Riederer 31

Future

5HT2A receptors are also upregulated in dementia with Lewy bodies,Reference Cheng, Ferrier and Morris 29 a condition where dementia precedes any motor symptoms, whereas in Parkinson’s disease, the motor symptoms precede the dementia.Reference Stinton, McKeith and Taylor 52 Reference Petrova, Mehrabian-Spasova, Aarsland, Raycheva and Traykov 56 Visual hallucinations are a prominent feature in many patients who have dementia with Lewy bodies,Reference Stinton, McKeith and Taylor 52 Reference Petrova, Mehrabian-Spasova, Aarsland, Raycheva and Traykov 56 so it is rational to hypothesize that these psychotic symptoms might also be treatable with pimavanserin. Indeed, studies are underway to investigate this possibility. Psychotic symptoms also accompany the dementia of Alzheimer’s disease,Reference Cummings 1 , Reference Stahl 34 whether comorbid with Parkinson’s Disease or not, and could possibly be a therapeutic target for pimavanserin as well.Reference Price, Bonhaus and McFarland 57 Finally, pimavanserin and all 5HT2A antagonists enhance slow-wave sleep,Reference Ancoli-Israel, Vanover, Weiner, Davis and van Kammen 58 and there may be therapeutic implications of this action as well.

References

1. Cummings, JL. Behavioral complications of drug treatment of Parkinson’s disease. J Am Geriatr Soc. 1991; 39(7): 708716.CrossRefGoogle ScholarPubMed
2. Chang, A, Fox, SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. In press. DOI: 10.1007/s40265-016-0600-5.Google Scholar
3. Goldman, JG, Holden, S. Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol. 2014; 16(3): 281.CrossRefGoogle ScholarPubMed
4. Goldman, JG, Vaughan, CL, Goetz, CG. An update expert opinion on management and research strategies in Parkinson’s disease psychosis. Expert Opin Pharmacother. 2011; 12(13): 20092024.Google Scholar
5. Paponabarrage, J, Martinez-Horta, S, Fernández de Bobadilla, R, et al. Minor hallucinations occur in drug-naïve Parkinson’s disease patients, even from the premotor phase. Mov Disord. 2016; 31(1): 4552.Google Scholar
6. Vaillancourt, DE, Schonfeld, D, Kwak, Y, Bohnen, NI, Seidler, R. Dopamine overdose hypothesis: evidence and clinical implications. Mov Disord. 2013; 28(14): 19201929.Google Scholar
7. MacDonald, AA, Mondhi, O, Seergobin, KN, Ganjavi, H, Tamjeedi, R, MacDonald, PA. Parkinson’s disease duration determines effect of dopaminergic therapy on ventral striatum function. Mov Disord. 2013; 28(2): 153160.CrossRefGoogle Scholar
8. Joutsa, J, Johansson, J, Seppänen, M, Nopenen, T, Kaasinen, V. Dorsal-to-ventral shift in midbrain dopaminergic projections and increased thalamic/raphe serotonergic function in early Parkinson disease. J Nucl Med. 2015; 56(7): 10361041.Google Scholar
9. Klein, C, Prokhorov, T, Miniovitz, A, Dobronevsky, E, Rabey, JM. Admission of Parkinsonian patients to a neurological ward in a community hospital. J Neural Transm (Vienna). 2009; 116(11): 15091512.CrossRefGoogle Scholar
10. Goetz, CG, Stebbins, GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology. 1993; 43(11): 22272229.Google Scholar
11. Aarsland, D, Larsen, JP, Tandberg, E, Laake, K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc. 2000; 48(8): 938942.CrossRefGoogle ScholarPubMed
12. Goetz, CG, Stebbins, GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology. 1995; 45(4): 669671.Google Scholar
13. Forsaa, EB, Larsen, JP, Wentzel-Larsen, T, Alves, G. What predicts mortality in Parkinson’s disease? A prospective population-based long-term study. Neurology. 2010; 75(14): 12701276.CrossRefGoogle ScholarPubMed
14. Schneider, LS, Dagerman, KS, Insel, P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005; 294(15): 19341943.CrossRefGoogle ScholarPubMed
15. Ballard, C, Isaacson, S, Mills, R, et al. Impact of current antipsychotic medications on comparative mortality and adverse events in people with Parkinson disease psychosis. J Am Med Dir Assoc. 2015; 16(10): 898.Google Scholar
16. Birkmayer, W, Birkmayer, JD. Dopamine action and disorders of neurotransmitter balance. Gerontology. 1987; 33(3–4): 168171.CrossRefGoogle ScholarPubMed
17. Ravina, B, Marek, K, Eberly, S, et al. Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Mov Disord. 2012; 27(11): 13921397.Google Scholar
18. Kordower, JH, Olanaw, CW, Dodiya, HB, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013; 136(Pt 8): 24192431.Google Scholar
19. Barone, P. Neurotransmission in Parkinson’s disease: beyond dopamine. Eur J Neurol.. 2010; 17(3): 364376.CrossRefGoogle ScholarPubMed
20. Huot, P, Fox, . The serotonergic system in motor and non-motor manifestations of Parkinson’s disease., Exp Brain Res. 2013; 230(4): 463476.CrossRefGoogle ScholarPubMed
21. Halliday, GM, Blumbergs, PC, Cotton, RGH, Blessing, WW, Geffen, LB. Loss of brainstem serotonin- and substance Pcontaining neurons in Parkinson’s disease. Brain Res. 1990; 510(1): 104107.CrossRefGoogle ScholarPubMed
22. Fox, SH, Chuang, R, Brotchie, JM. Serotonin and Parkinson’s disease: on movement, mood and madness. Mov Disord. 2009; 24(9): 12551266.CrossRefGoogle ScholarPubMed
23. Huot, P, Hohnston, TH, Darr, T, et al. Increased 5HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord. 2010; 25(10): 13991408.CrossRefGoogle ScholarPubMed
24. Ballenger, B, Strafella, AP, van Eimeren, T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2000; 67(4): 416421.Google Scholar
25. Kerenyi, L, Ricaurte, GA, Schretlen, DJ, et al. Positron emission tomography of striatal serotonin transporters in Parkinson disease. Arch Neurol. 2003; 60(9): 12231229.Google Scholar
26. Kiferle, L, Cervolo, R, Petrozzi, L, et al. Visual hallucinations in Parkinson’s disease are not influenced by polymorphisms of serotonin 5HT2A receptor and transporter genes. Neurosci Lett. 2007; 422(3): 228231.CrossRefGoogle Scholar
27. Albin, RL, Koeppe, RA, Bohnen, NI, Wernette, K, Kilbourn, MA, Frey, KA. Spared caudal brainstem SERT binding in early Parkinson’s disease. J Cereb Blood Flow Metab. 2008; 28(3): 441444.CrossRefGoogle ScholarPubMed
28. Ohno, Y, Shimizu, S, Tokudome, K, Kunisawa, N, Sasa, M. New insight into the therapeutic role of the serotonergic system in Parkinson’s disease. Prog Neurobiol. 2015; 134: 104121.CrossRefGoogle ScholarPubMed
29. Cheng, AVT, Ferrier, IN, Morris, CM, et al. Cortical serotonin-S2 receptor binding in Lewy Body dementia, Alzheimer’s and Parkinson’s diseases. J Neurol Sci. 1991; 106(1): 5055.Google Scholar
30. Politis, M, Miccolini, F. Serotonin in Parkinson’s disease. Behav Brain Res. 2015; 277: 136145.Google Scholar
31. Birkmayer, W, Danielczyk, W, Neumayer, E, Riederer, P. Nucleus ruber and L-Dopa psychosis: biochemical post-mortem findings. J Neural Transm. 1974; 35(2): 93116.CrossRefGoogle ScholarPubMed
32. Zahodne, LB, Fernandez, HH. Pathophysiology and treatment of psychosis in Parkinson’s disease: a review. Drugs Aging. 2008; 25(8): 665682.Google Scholar
33. Desmarais, P, Massoud, F, Filion, J, Nguyen, QD, Bajsarowicz, P. Quetiapine for psychosis in Parkinson Disease and neurodegenerative parkinsonian disorders: a systematic review. J Geriatr Psychiatry Neurol. 2016; 29(4): 227236.Google Scholar
34. Stahl, SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge, UK: Cambridge University Press; 2013.Google Scholar
35. Hubbard, D, Hacksell, U, McFarland, K. Behavioral effects of clozapine, pimavanserin and quetiapine in rodent models of Parkinson’s disease and Parkinson’s disease psychosis: evaluation of therapeutic ratios. Behav Pharmacol. 2013; 24(7): 628632.Google Scholar
36. Vanover, KE, Weiner, DM, Makhay, M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006; 317(2): 910918.Google Scholar
37. Cummings, J, Isaacson, S, Mills, R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014; 383(9916): 533540.Google Scholar
38. Hermanowicz, S, Hermanowicz, N. The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson’s disease. Expert Rev Neurother. 2016; 16(6): 625633.Google Scholar
39. Friedman, JH. Pimavanserin for the treatment of Parkinson’s disease psychosis. Expert Opin Pharmacother. 2013; 14(14): 19691975.CrossRefGoogle ScholarPubMed
40. Meltzer, HY, Mills, R, Revell, S, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology. 2010; 35(4): 881892.CrossRefGoogle ScholarPubMed
41. Vanover, KE, Robbins-Weilert, D, Wilbraham, DG, et al. Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol. 2007; 47(6): 704714.Google Scholar
42. Nordstrom, A-L, Mansson, M, Jovanovic, H, et al. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008; 11(2): 163171.Google Scholar
43. Li, Z, Ichikawa, J, Huang, M, Prus, AJ, Dai, J, Meltzer, HY. ACP-103, a 5-HT2A/2C inverse agonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Psychopharmacology (Berl). 2005; 183(2): 144153.Google Scholar
44. Kenakin, T. Inverse, protean, and ligand-selective agonism: matters of receptor conformation. FASEB J. 2001; 15(3): 598611.Google Scholar
45. Brink, CB, Harvey, BH, Bodenstein, J, Venter, DP, Oliver, DW. Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology. Br J Clin Pharmacol. 2003; 57(4): 373387.Google Scholar
46. Weiner, DM, Burstein, ES, Nash, N, et al. 5-Hydroxytryptamine 2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther. 2001; 299(1): 268276.Google Scholar
47. Laoutidis, ZG, Luckhaus, C. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014; 17(5): 823832.Google Scholar
48. Gardell, LR, Vanover, KE, Pounds, L, et al. ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models. J Pharmacol Exp Ther. 2007; 322(2): 862870.Google Scholar
49. Meltzer, HY, Elkis, H, Vanover, K, et al. Pimavanserin, a selective serotonin (5HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res. 2012; 141(2–3): 144152.CrossRefGoogle Scholar
50. Sadzot, B, Baraban, JM, Glennon, RA, et al. Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis. Psychopharmacology (Berl). 1989; 98(4): 494499.Google Scholar
51. McClue, SJ, Brazell, C, Stahl, SM. Hallucinogenic drugs are partial agonists of the human platelet shape change response: a physiological model of the 5-HT2 receptor. Biol Psychiatry. 1989; 26(3): 297302.Google Scholar
52. Stinton, C, McKeith, I, Taylor, JP, et al. Pharmacological management of Lew body dementia: a systematic review and meta-analysis. Am J Psychiatry. 2015; 172(8): 731742.Google Scholar
53. Boot, BP. Comprehensive treatment of dementia with Lewy bodies. Alzheimers Res Ther. 2015; 7(1): 4552.Google Scholar
54. Hogan, DB, Fiest, KM, Roberts, JI, et al. The prevalence and incidence of dementia with Lewy bodies: a systematic review. Can J Neurol Sci. 2016; 43(Suppl 1): S83S95.Google Scholar
55. Jacobson, SA, Morshed, T, Dugger, BN, et al. Plaques and tangles as well as Lewy-type alpha synucleinopathy are associated with formed visual hallucinations. Parkinsonism Relat Disord. 2014; 20(9): 10091014.Google Scholar
56. Petrova, M, Mehrabian-Spasova, S, Aarsland, D, Raycheva, M, Traykov, L. Clinical and neuropsychological differences between mild Parkinson’s disease dementia and dementia with Lewy bodies. Dement Geriatr Cogn Dis Extra. 2015; 5(2): 212220.CrossRefGoogle ScholarPubMed
57. Price, DL, Bonhaus, DW, McFarland, K. Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease. Behav Pharmacol. 2012; 23(4): 426433.Google Scholar
58. Ancoli-Israel, S, Vanover, KE, Weiner, DM, Davis, RE, van Kammen, DP. Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. 2011; 12(2): 134141.Google Scholar
Figure 0

Figure 1 Mechanism of action of pimavanserin. Shown here are the binding properties of pimavanserin, namely potent antagonist actions at serotonin 5HT2A receptors, sometimes called inverse agonist actions, and less potent antagonist/inverse agonist actions at 5HT2C receptors. Note that there is no notable binding to D2 dopamine receptors or any other neurotransmitter receptors.