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.

Inclusion criteria

• Willing and able to give informed consent for participation in the research
• Aged 18-45 years
• Good vision and hearing
• Body mass index (BMI) within the range of 18-35kg/m2 (This is to ensure an appropriate pharmacokinetic profile for pimavanserin is achieved by all participants)
• Sufficiently fluent in English to understand tasks
• Willing to avoid drinking any alcohol the day before the research visit

Exclusion criteria

• Currently receiving or seeking treatment for any mental health condition
• Any past or current history of severe and/or serious psychiatric disorder, including but not limited to schizophrenia, psychosis, bipolar affective disorder, severe major depressive disorder, obsessive compulsive disorder (covered in SCID-5 assessment in screening procedures)
• ADHD requiring treatment with stimulant or other centrally-acting drugs
• Regular alcohol consumption of more than 21 units per week
• A head injury causing concussion or unconsciousness in the past 6 months
• Pregnancy / intention to become pregnant during the study or breastfeeding
• Any use of recreational drugs in the last three months
• Participation in any other drug study in the last three months
• Participation in any other study with the same tasks in the last year
• History of cardiac disease or cardiac arrhythmias
• Prolonged QTc interval on baseline ECG
• Current usage of other drugs known to prolong QT interval including Class 1A or 3 antiarrhythmics, e.g. certain antibiotics (getifloxacin, moxifloxacin)
• Current use of drugs that inhibit CYP3A4 (eg Clarithromycin. Diltiazem. Erythromycin. Fluconazole). Participants will be asked to avoid grapefruit juice in the week before the study.
• Current use of psychoactive medication that in the opinion of the Chief Investigator may interfere with the study measures
• History of, or current medical condition(s) which, in the opinion of the Investigator may interfere with the safety of the participant or the scientific integrity of the study, including epilepsy/seizures, brain injury, severe hepatic or renal disease, severe gastro-intestinal problems, Central Nervous System (CNS) tumours, severe neurological problems (e.g. Parkinson's disease; blackouts requiring hospitalisation);
• Any physical (including visual and auditory), cognitive or language impairment that would make complying with the study protocol challenging
• Excessive caffeine consumption, i.e., consumption higher than 8 cups of standard caffeinated drinks (tea, instant coffee) or higher than 6 cups of stronger coffee or other drinks containing methylxanthines such as coca cola or Red Bull per day;
• Smoking >10 cigarettes per day; or equivalent nicotine consumption
• Participant who is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the chief investigator.
• Inability to ingest up to 95mg of lactose

Additional Exclusion Criteria for Participants in the Sleep Study Cohort:

• Unable to undergo cardiac monitoring
• Unable to wear the sleep patch device for full monitoring period
• Implanted neurostimulator