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

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.

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, ^{1 – 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; ^{1 – 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; ^{1 – 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. ^{1 – 4 , 6 – 8} Whatever the cause of PDP, it is clear that its onset is not good news, since it is associated with dementia ^{1 – 8} and predicts repeated hospitalizations, ⁹ nursing home placement, ^{10 , 11} and death. ^{12 , 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. ^{2 – 4 , 14 , 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. ^{2 – 4 , 6 – 8 , 16 – 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. ^{2 – 4 , 6 , 32 , 33} Originally, the notion was that antipsychotics such as quetiapine or clozapine worked in PDP by blocking D2 dopamine receptors, ^{2 – 4 , 32 , 33} just as these drugs are thought to work in schizophrenia. ³⁴ However, a novel line of investigation now suggests that it is actually the potent serotonin 5HT2A antagonist properties of quetiapine and clozapine, ^{34 , 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 actions ³⁶ —has now been proven effective in PDP. ^{37 – 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). 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 PDP ^{37 – 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 receptor ^{41 , 42} are not effective in PDP. ^{37 – 40} However, twice this dose is effective, ^{37 – 40} and this higher dose—the one that is approved for treatment of PDP by the FDA—not only saturates 5HT2A receptors, ⁴² but also recruits substantial if lesser degrees of occupancy of 5HT2C receptors. 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. 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. ^{34 , 36 , 44 , 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.” ^{34 , 44 , 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 agonist ³⁶ also show that all the other atypical antipsychotics that interact at 5HT2A receptors are also inverse agonists. ⁴⁶ Atypical antipsychotics have been traditionally called 5HT2A antagonists, not inverse agonists. 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 receptors ³⁴ and all atypical antipsychotics block both D2 and 5HT2A receptors, ³⁴ pimavanserin is the first 5HT2A/2C antagonist lacking D2 antagonist properties ⁴⁶ that has been proven effective in psychosis, specifically PDP. ^{37 – 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. ^{2 – 4 , 6 – 8 , 32 , 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, ³⁴ but the evidence that 5HT2A receptors mediate antipsychotic actions was sparse. ^{34 , 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. ^{48 , 49} Thus, it was a bit of a surprise that pimavanserin monotherapy, with its 5HT2A/2C antagonist properties, showed antipsychotic efficacy in PDP ^{37 – 40} without blocking D2 receptors. 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. ^{6 – 8 , 16 – 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. ^{1 – 6 , 17 , 18} Less well appreciated is that both serotonin and dopamine neurons degenerate in Parkinson’s disease. ^{16 , 20 – 22} Although degeneration of dopamine neurons in the substantia nigra is linked to motor symptoms in Parkinson’s disease, ^{1 , 6 – 8 , 17 , 18} loss of serotonin neurons is not. ^{16 , 20 – 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. ^{23 – 27} That is, excessive stimulation of these receptors is thought to result in psychotic symptoms, especially visual hallucinations, which are the hallmark of PDP. ^{23 – 31 , 50} Indeed, hallucinogenic drugs cause striking visual hallucinations by stimulating these very same 5HT2A receptors. ^{50 , 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. ^{23 – 31 , 50 , 51} Also, 5HT2A receptors in the cortex regulate the downstream release of dopamine, ³⁴ which has been hypothesized to have undergone a dorsal-to-ventral shift in the striatum in PDP. ⁸ Blocking these receptors could theoretically restore the correct balance by partially reversing this shift. ^{8 , 23 – 31}

Future

5HT2A receptors are also upregulated in dementia with Lewy bodies, ²⁹ a condition where dementia precedes any motor symptoms, whereas in Parkinson’s disease, the motor symptoms precede the dementia. ^{52 – 56} Visual hallucinations are a prominent feature in many patients who have dementia with Lewy bodies, ^{52 – 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, ^{1 , 34} whether comorbid with Parkinson’s Disease or not, and could possibly be a therapeutic target for pimavanserin as well. ⁵⁷ Finally, pimavanserin and all 5HT2A antagonists enhance slow-wave sleep, ⁵⁸ and there may be therapeutic implications of this action as well.