Background

Oxytocin is a peptide hormone involved in social bonding, reproduction, and childbirth. Defects in oxytocin biology have been implicated in neurodegenerative disorders ranging from frontotemporal dementia to Huntington's disease (e.g. Bergh et al., 2022; Saiz-Rodgriguez et al., 2022).

Oxytocin therapy is approved for inducing labor, controlling postpartum bleeding, and aiding breastfeeding. It is given by injection, or as an intranasal spray. Low-dose oxytocin nasal sprays are available without prescription in the U.S.

Nasal oxytocin has been widely studied for its effects on social behavior. In healthy adults or people with autism, intranasal oxytocin acutely improves recognition of emotional and social cues, and enhances empathy and cooperative behavior. It can also stimulate aggressive behavior in some contexts. The nasal spray delivers oxytocin to the brain, where it is reported to last for several hours (see review by Quintana et al., 2021).

Oxytocin is proposed as a symptomatic treatment for people with frontotemporal dementia, where damage to the frontal and temporal lobes impairs emotional processing, social cognition, and behavior. Loss of empathy is a hallmark symptom of behavioral variant frontotemporal dementia. These patients also show deficits in recognizing facial expressions and verbal emotional cues, and lose insight into what others think or might do. Indifference to even close family members is a major challenge for caregivers. There are no treatments for these social behavioral problems in people with FTD. However, plasma levels of oxytocin have been reported to be unrelated to social cognition or behavior in these diseases (Johnson et al., 2022).

In Alzheimer’s disease, preclinical studies in mouse models have reported beneficial effects of nasal oxytocin on pathology and memory (Takahashi et al., 2022; El-Ganainy et al., 2022).

Findings

From September 2009 to November 2010, an academic-sponsored pilot study in Ontario, Canada, tested nasal oxytocin in 20 patients with a clinical diagnosis of behavioral variant FTD. Participants in the crossover trial received a single dose of 24 International Units of oxytocin or placebo, delivered intranasally. Eight hours and one week after dosing, they completed tasks related to recognition of emotional cues from others, and neuropsychiatric behaviors. Eight hours post-dose, patients had significant improvement in Neuropsychiatric Inventory scores, and trended toward improvement in the Frontal Behavioral Inventory, compared with baseline and with placebo. Oxytocin also reduced recognition of negative facial expressions of anger or fear (Jesso et al., 2011; Jun 2012 conference news). The investigators noted no effects on any endpoint after one week, and no significant adverse effects of the drug at any time.  

Between June 2011 and October 2013, a Phase 1 study was completed at the same Canadian center. It enrolled 23 FTD patients to evaluate the safety and tolerability of 24, 48, or 72 IU of nasal oxytocin, given twice daily for one week. Results are published (Finger et al., 2015). All three doses were safe and well-tolerated. No serious adverse events occurred, although one-third of treated patients showed higher levels of inappropriate sexual behaviors. Efficacy outcomes suggested possible improvements in apathy and empathy, especially at the highest dose.

The same Canadian group performed a Phase 2 study between September 2013 and December 2017, measuring the effects of oxytocin on functional MRI imaging while participants viewed and imitated different facial expressions. The trial involved 28 FTD patients, who received a one-time dose of 72 IU intranasal oxytocin or placebo in a crossover design. According to published results, oxytocin treatment increased BOLD signals in regions of the brain associated with facial expression processing and empathy (Oliver et al., 2020).

In January 2018, a multicenter Phase 2 safety and efficacy trial called FOXY began. Initially, the study will compare daily and intermittent dosing in 112 patients. In the crossover design, participants will receive six weeks of 72 IU daily, every other day, or every third day, or placebo, against a primary outcome of change in the NPI apathy/indifference domain score. After that, an additional 40 patients will be enrolled to the most promising regimen for an efficacy assessment. Other endpoints include facial expression recognition, CSF oxytocin levels, and ratings of behavior based on videotaped interactions. The study, running at 11 centers across Canada and the U.S., is expected to wrap up in January 2023. The protocol is published (Finger et al., 2018).

Nasal oxytocin is under investigation for autism, schizophrenia, pain, substance use disorders, obesity, , personality disorders, PTSD and other conditions (e.g. see Guastella et al., 2022; Korann et al., 2022).

For details on nasal oxytocin trials in FTD, see clinicaltrials.gov.