Investigating the Neuropsychological Effects of 5-HT2a Antagonism

Serotonin (5-HT) 2A receptors are widely expressed in the human brain in areas involved in cognition and emotion and are thought to play a key role in the aetiology of a number of psychiatric disorders, including depression. Medication free patients with depression have increased 5-HT2A receptor binding (Bhagwagar et al., 2006) and many effective antidepressant treatments are antagonists of the 5-HT2A receptor, including mirtazapine, olanzapine, quetiapine and aripiprazole. Conversely, psychedelic drugs such as psilocybin are powerful agonists of the 5-HT2A receptor, and are gaining traction as a novel approach to the treatment of depression (Goodwin et al 2022).

Animal and human studies suggest that the 5-HT2A receptor plays a key role in memory and cognitive flexibility. Activation of the 5-HT2A receptor in animals has been shown to improve novel object memory, with a particular effect on the consolidation of memories (Zhang et al 2012). There is also an increasing body of evidence suggesting that 5-HT2A agonists may increase cognitive flexibility, and this is thought to be one mechanism through which psychedelics may exert their rapid-onset and sustained antidepressant effects (Luppi et al 2024). For example, the non-selective 5-HT2A receptor agonist lysergic acid diethylamide (LSD) has been shown to increase learning rates and exploratory behaviour on a probabilistic reversal learning task in healthy volunteers (Kanen et al 2022), which is consistent with increased flexibility and a destabilisation of existing beliefs/priors.

However, the existing evidence base is somewhat mixed, with contradictory findings regarding the direction of effects of 5-HT2A activation on cognition. It is likely that this is in part due to the non-selective nature of the pharmacological probes used, with many having effects on serotonin receptors beyond 5-HT2A and on other neurotransmitter systems, including dopamine. There is also evidence that 5-HT2A agonists that have psychedelic properties may have a unique profile of effects on intracellular 5-HT2A receptors (Vargas et al 2023), which further complicates the interpretation of the existing evidence base.

The development of highly selective 5-HT2A antagonists offers the opportunity to further understand the role played by this receptor subtype in cognition. Pimavanserin has a relatively selective pharmacological action; it is a potent inverse agonist of the 5-HT2A receptor and also has around 40-fold less potent activity at 5-HT2C receptors. Pimavanserin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of hallucinations and delusions associated with psychosis in people with Parkinson's disease with a recommended dose range between 34-40mg once daily. Whilst at this dose it is likely that both 5-HT2A and 5-HT2C receptors are engaged, Positron Emission Tomography (PET) studies have demonstrated that with lower doses (10-20mg) it is possible to achieve full saturation of the 5-HT2A receptor without action at the 5-HT2C receptor (Nordstrom et al 2007). The effects of pimavaserin have also been tested in patients with depression in a study in which it was administered as an adjunct to standard antidepressant treatment. Whilst there were some initial positive findings of benefits on depressive symptoms, impulsivity, irritability, anxiety, insomnia, daytime sleepiness, and sexual and psychosocial functioning (Fava et al 2019), subsequent Phase 3 trials were less positive (Dirks et al 2022). Pimavanserin is well tolerated with minimal side effects; the most common side effects reported in the trials were dry mouth, nausea and headache. Low dose pimavanserin therefore offers the opportunity to safely and selectively manipulate the function of 5-HT2A receptors in the human brain.

In this study, the investigators will use pimavanserin as a pharmacological probe to further investigate the role of the 5-HT2A receptor in human cognition. Healthy volunteers will be randomised to receive a single dose (10mg) of pimavanserin or placebo. Four hours later (once the drug has reached peak plasma concentration), they will complete a battery of cognitive tests designed to measure learning and memory, cognitive flexibility and emotional processing. The investigators will also collect sleep monitoring data from a sub-set of participants for a feasibility study. The monitoring of sleep is a useful metric to consider as it may uncover further details pimavanserin's mechanism of action.