Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Pimavanserin: An Inverse Agonist Antipsychotic Drug

Robert H. Howland, MD

Abstract

Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21–24.]

Abstract

Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21–24.]

Exploring psychotherapeutic issues and agents in clinical practice

The atypical antipsychotic drug pimavanserin (ACP-103) was recently approved by the U.S. Food and Drug Administration (FDA) with the brand name Nuplazid® for the treatment of hallucinations and delusions associated with Parkinson's disease (Cummings et al., 2014; Meltzer et al., 2010). Unlike other marketed antipsychotic drugs, pimavanserin has negligible binding effects at dopamine D2 receptors (Hacksell, Burstein, McFarland, Mills, & Williams, 2014). In this article, I will explain how this drug treats psychosis and why its mechanism is important to understand.

Mechanism of Action of Pimavanserin

Approximately all clinically useful antipsychotic drugs have known activity as D2 receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor (Weiner et al., 2001). Pimavanserin is an inverse agonist at the 5HT2A receptor and serotonin-2C (5HT2C) receptor, although its 5HT2C binding affinity is much lower than its binding affinity to the 5HT2A receptor. Pimavanserin also has a low binding affinity to the sigma 1 receptor, but no significant binding to any other receptors.

A receptor is said to have intrinsic or constitutive (basal) activity when it is active (i.e., signaling) in the absence of a ligand that can bind to and stimulate its signaling activity. The 5HT2A and 5HT2C receptors have basal level activity in the absence of serotonin. An agonist drug binding to an intrinsically active receptor will increase receptor activity above its basal level. A full agonist drug will maximize the receptor's activity, whereas a partial agonist drug will increase receptor activity to a lesser extent. An inverse agonist drug reduces the activity of an intrinsically active receptor below its basal level, and also blocks the effects of an agonist drug at the receptor. A neutral antagonist drug binding to an intrinsically active receptor has no influence on the receptor's basal activity level, but blocks the effects of an agonist or inverse agonist drug at the receptor.

Treatment of Parkinson's Disease Psychosis

By blocking dopamine receptors, antipsychotic drugs can cause extrapyramidal (i.e., Parkinsonian) motor side effects (EPS), such as akathisia, tremors, dystonias, muscle rigidity, and bradykinesia. For this reason, antipsychotic drugs are usually avoided in patients with Parkinson's disease. Parkinson's disease is associated with high rates of psychosis, posing a dilemma for the use of antipsychotic drugs (Seppi et al., 2011). Low doses of clozapine (Clozaril®) or quetiapine (Seroquel®) have been most commonly advocated for treating these patients, because these drugs are believed to have a lower risk for EPS compared to other antipsychotic drugs (Seppi et al., 2011). Controlled studies of clozapine, but not quetiapine, have shown benefit for Parkinson's disease psychosis, although clozapine is not a popular drug to use because of its adverse effect profile and requirement for laboratory monitoring (Cummings et al., 2014).

The degree of D2 receptor blockade of an antipsychotic drug is associated with higher rates of EPS. By contrast, lower rates of EPS occur among antipsychotic drugs with inverse agonist 5HT2A receptor effects (Weiner et al., 2001), and this pharmacological characteristic is common among atypical antipsychotic drugs (Meltzer & Massey, 2011). Moreover, D2 receptor antagonism and 5HT2A receptor inverse agonism appear to be independent mechanisms mediating their antipsychotic efficacy (Weiner et al., 2001). As a 5HT2A inverse agonist with negligible D2 receptor effects, pimavanserin is able to treat psychosis in Parkinson's disease without exacerbating motor symptoms.

Can Pimavanserin Treat Other Psychotic Disorders?

Pimavanserin will become the standard of pharmacology care for Parkinson's disease psychosis. Can this drug effectively treat psychotic symptoms in other neuropsychiatric disorders? Lewy body dementia (LBD) has clinical and pathological features that overlap with those of Alzheimer's disease and Parkinson's disease (Howland, 2015). In LBD, the progressive decline in cognitive function is accompanied by the development of Parkinsonian symptoms. Two features of LBD are day-to-day fluctuations in cognitive function and the presence of visual hallucinations. Patients with LBD are extremely sensitive to the adverse effects of antipsychotic drugs. Pimavanserin may be an appropriate treatment option for LBD, but has not been studied in these patients. A clinical trial of pimavanserin for Alzheimer's disease psychosis is currently in progress (NCT02035553; access http://www.ClinicalTrials.gov).

Can pimavanserin treat psychotic symptoms in schizophrenia? Interest in a role for serotonin receptor systems in the pathophysiology of schizophrenia was based on the observation that the hallucinogen drug lysergic acid diethylamide (LSD) is a potent agonist at the 5HT2A receptor (Rasmussen et al., 2010). 5HT2A receptor agonism is a pharmacological property common to hallucinogenic drugs (Erritzoe et al., 2011) and may explain why certain drugs can be associated with adverse neuropsychiatric effects. The drugs mefloquine (Lariam®), used to treat malaria, and efavirenz (Sustiva®), used to treat HIV infection, are partial agonists at the 5HT2A receptor. Both drugs can cause adverse neuropsychiatric effects, including psychotic symptoms. There is evidence from autopsy and brain imaging studies that 5HT2A receptor binding is decreased in the frontal cortex of patients with schizophrenia (Rasmussen et al., 2010). Despite sharing the clinical symptoms of psychosis, however, the pathophysiology of schizophrenia and Parkinson's disease psychosis are likely to be different.

Preclinical studies suggested that adjunctive use of pimavanserin may result in enhanced antipsychotic efficacy and reduced adverse effects of haloperidol (Haldol®) and risperidone (Risperdal®). Two small placebo-controlled phase II studies (one in healthy participants and one in patients with schizophrenia) found that pimavanserin reduced symptoms of akathisia associated with the use of haloperidol, but did not improve psychotic symptoms in the schizophrenia study (Abbas & Roth, 2008). A randomized placebo-controlled 6-week study of 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms found that pimavanserin augmentation (compared to placebo augmentation) enhanced the efficacy and reduced the side effects of low-dose risperidone (2 mg per day) and reduced akathisia associated with low-dose haloperidol (2 mg per day), but did not enhance the efficacy of low-dose haloperidol (Meltzer et al., 2012). To my knowledge, no monotherapy studies (using pimavanserin alone) have been conducted or are in progress for the treatment of schizophrenia.

Whether pimavanserin can treat psychotic symptoms in other disorders, such as psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, I would predict that pimavanserin may be effective for treating symptoms associated with the use of LSD, methylenedioxymethamphetamine (MDMA), or other hallucinogen drugs. Many atypical antipsychotic drugs have antidepressant effects, and some are FDA approved as augmentation therapies for treating depression, but the therapeutic potential of pimavanserin for the treatment of depression is unknown. Psilocybin, a prodrug that is converted to the 5HT2A agonist drug psilocin, may have antidepressant effects based on this receptor effect (Carhart-Harris et al., 2016). As a 5HT2A receptor inverse agonist, it is possible that pimavanserin may have adverse mood effects.

Treatment of Akathisia and Negative Symptoms

Pimavanserin did not worsen motor symptoms in the Parkinson's disease psychosis studies (there were small non-significant improvements in motor performance) (Cummings et al., 2014; Meltzer et al., 2010). The studies described previously (Abbas & Roth, 2008; Meltzer et al., 2012) suggest that it can reduce symptoms of akathisia associated with antipsychotic drugs. The antidepressant drug mirtazapine (Remeron®), an antagonist at the 5HT2A receptor and an inverse agonist at the 5HT2C receptor, can reduce akathisia associated with antipsychotic drugs (Hieber, Dellenbaugh, & Nelson, 2008). Mirtazapine is a derivative analog of the antidepressant drug mianserin (available in some countries, but not the United States). A few reports suggest that mianserin and mirtazapine may treat Parkinson's disease psychosis (Godschalx-Dekker & Siegers, 2014; Ikeguchi & Kuroda, 1995; Tagai et al., 2013), although neither drug has been systematically studied for these patients. Mirtazapine, however, has benefit for improving negative symptoms in patients with schizophrenia when added to antipsychotic medication (Vidal, Reese, Fischer, Chiapelli, & Himelhoch, 2015). These studies support an important mechanistic role for 5HT2A and 5HT2C receptor systems in the treatment of akathisia and negative symptoms. Further study of pimavanserin in these areas is warranted.

Safety and Tolerability of Pimavanserin

Pimavanserin was relatively well tolerated in the Parkinson's disease psychosis studies (Cummings et al., 2014; Meltzer et al., 2010). Mean participant age was approximately 70 years. The most common adverse effects of pimavanserin (greater than placebo) were peripheral edema (7%), nausea (7%), confusion (6%), hallucinations (5%), constipation (4%), and gait disturbance (2%). Hallucinations as a potential adverse effect may be related to aberrant drug effects on the 5HT2A receptor system. Although pimavanserin is an inverse agonist, the drug may have agonist properties in some patients, resulting in a hallucinogen-like drug effect. Genetic polymorphisms of the 5HT2A receptor can be detected using pharmacogenetic tests (Howland, 2014), and these tests should be investigated for evaluating differences in efficacy or tolerability of pimavanserin in Parkinson's disease psychosis.

Pimavanserin prolongs the QT interval, an effect described as a potential cardiac safety concern for other antipsychotic drugs as well as some antidepressant drugs (Hasnain et al., 2014; Vieweg et al., 2012). Because depression is common in patients with Parkinson's disease, the use and choice of antidepressant medication should include an assessment of the risk for drug–drug cardiac interactions.

Weight gain and adverse metabolic effects were not observed with pimavanserin, but these studies were only 4 to 6 weeks in duration (Cummings et al., 2014; Meltzer et al., 2010). Pimavanserin is an inverse agonist at the 5HT2C receptor, although with a lower affinity compared to its binding to the 5HT2A receptor. Lorcaserin (Belviq®) is a selective agonist drug that stimulates the 5HT2C receptor and is FDA approved for the treatment of obesity (Howland, 2013). Activation of the 5HT2C receptor decreases food intake by increasing satiety and decreasing hunger. A role for the 5HT2A receptor system in the regulation of body weight also has been suggested, and 5HT2A receptor binding was found to predict weight gain in patients with schizophrenia who were treated with quetiapine (Rasmussen et al., 2014). Mirtazapine is associated with weight gain. Based on these pharmacological considerations, adverse weight and metabolic effects are therefore likely to be a concern with longer term use of pimavanserin.

Conclusion

The unique mechanism of action of 5HT2A inverse agonism with negligible dopamine receptor effects highlights the known and potential therapeutic uses of pimavanserin. Nurses should become familiar with the pharmacological and clinical profile of this interesting drug.

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Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

10.3928/02793695-20160523-01

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