Evaluating pimavanserin as a treatment for psychiatric disorders: A pharmacological property in search of an indication

Abstract

Introduction: Pimavanserin is FDA-approved to treat hallucinations and delusions associated with Parkinson's disease psychosis. As a potent 5-HT 2A inverse agonist/antagonist, it could be efficacious in other psychiatric disorders. Recently, several studies have investigated this potential. Areas covered: The authors review the efficacy and adverse effects of pimavanserin for hallucinations in dementia, major depression, and schizophrenia. Expert opinion: Two controlled studies suggest pimavanserin has potential as a treatment for hallucinations in dementia. In patients with depression who did not respond to antidepressant treatment, pimavanserin augmentation was efficacious in a phase 2 study. Pimavanserin augmentation also alleviated sexual side effects of SSRI and SSNI. However, Acadia Pharmaceuticals stated in a press release that it does not plan further antidepressant trials based on its phase 3 trial, which showed a nonsignificant trend toward an antidepressant effect. Since almost all existing antipsychotics fail to substantially benefit negative symptoms, better treatments are needed. Pimavanserin augmentation of antipsychotics did benefit negative symptoms (effect size≈0.2) but failed to reduce the total PANSS score significantly in two large, well-controlled double-blind studies. Pimavanserin has a good safety profile.

Emerging Treatments in Schizophrenia

“…Currently, 4 medications have shown promise for the treatment of symptoms in schizophrenia without blocking the postsynaptic dopamine receptor (Figure 6). 1,31,52,[54][55][56]…”

“…Pimavanserin has shown efficacy in one phase 2 study for predominant negative symptoms in schizophrenia. 56…”

“…Pimavanserin, which is approved for the treatment of Parkinson's psychosis, is currently being studied as an adjunctive treatment to antipsychotics to address negative and residual positive symptoms. 56 Pimavanserin is a potent inverse agonist and antagonist at 5-HT2A serotonin receptors and has less potent action at 5-HT2C receptors (see part C of Figure 6). This agent has no direct action at dopamine, adrenergic, histamine, serotonin, or cholinergic receptors.…”

Tardive Dyskinesia in Older Persons Taking Antipsychotics

“…Alternative mechanisms, including serotonin inverse agonism/antagonism in the absence of dopamine receptor blockade, agonism of TAAR1 receptors, and modulation of muscarinic cholinergic receptors, may provide different therapeutic approaches for patients who require a medication with an AP effect and avoid contributing to the risk of developing TD. [63][64][65][66]…”

“…Serotonin receptor inhibition has not been associated with TD, and selective inverse agonism/antagonism of 5HT receptors may be a therapeutic strategy that would mitigate the risk of TD. 63 Another potential preventative strategy is treatment of psychiatric disorders through selective agonism of the trace amine-associated receptor 1 (TAAR1), an approach that has recently been shown to improve symptoms of schizophrenia in adults and does not induce motor abnormalities in animal models. 64 Targeting the muscarinic system with a combination of xanomeline and trospium has also been proposed as a nondopaminergic strategy for mitigating TD risk.…”