Modulation of brain activation during executive functioning in autism with citalopram

Abstract

Adults with autism spectrum disorder (ASD) are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). However, there is limited evidence to support this practice. Therefore, it is crucial to understand the impact of SSRIs on brain function abnormalities in ASD. It has been suggested that some core symptoms in ASD are underpinned by deficits in executive functioning (EF). Hence, we investigated the role of the SSRI citalopram on EF networks in 19 right-handed adult males with ASD and 19 controls who did not differ in gender, age, IQ or handedness. We performed pharmacological functional magnetic resonance imaging to compare brain activity during two EF tasks (of response inhibition and sustained attention) after an acute dose of 20 mg citalopram or placebo using a randomised, double-blind, crossover design. Under placebo condition, individuals with ASD had abnormal brain activation in response inhibition regions, including inferior frontal, precentral and postcentral cortices and cerebellum. During sustained attention, individuals with ASD had abnormal brain activation in middle temporal cortex and (pre)cuneus. After citalopram administration, abnormal brain activation in inferior frontal cortex was ‘normalised’ and most of the other brain functional differences were ‘abolished’. Also, within ASD, the degree of responsivity in inferior frontal and postcentral cortices to SSRI challenge was related to plasma serotonin levels. These findings suggest that citalopram can ‘normalise’ atypical brain activation during EF in ASD. Future trials should investigate whether this shift in the biology of ASD is maintained after prolonged citalopram treatment, and if peripheral measures of serotonin predict treatment response.

Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter: A randomised placebo-controlled single-dose crossover trial

“…Interpreted with caution, our findings may suggest the citalopram treatment could have an impact on various symptoms of ASD (Williams et al, 2011). This is also in line with our previous report that acute citalopram challenge has an effect on executive function in ASD (Wichers et al, 2019). In addition, scrutiny of the individual responses indicates that not everyone in the ASD group responded to citalopram in the same direction.…”

“…Forty-two right-handed adult males (20 with ASD and 22 neurotypical controls, 18-60 years old) were enrolled in this study. Our sample size is determined based on our previous fMRI studies targeting 5-HT modulation (Daly et al, 2012(Daly et al, , 2014Wichers et al, 2019;Wong et al, 2020), and with power analysis (α = 0.05, 1 − β = 0.8, two-tailed) confirming that an overall sample of >24 individuals is sufficient to detect the group difference. Individuals with a clinical diagnosis of ASD were recruited through the National Adult Autism Service at the Maudsley Hospital where diagnosis is a multidisciplinary decision supported by the Autism Diagnostic Interview -Revised (where an informant is available) and/or the Autism Diagnostic Observation Schedule (ADOS) (Lord et al, 1989).…”

“…To support this contention, we previously reported preliminary evidence for central serotonin-based anomalies in ASD (Wichers et al, 2019), including the functional response to facial expressions of emotion (Daly et al, 2012). Specifically in a sample of male adults with and without ASD who all had intelligence quotient (IQ) above 70, we found that this relatively homogeneous sample of people with ASD had an atypical functional response at baseline.…”

Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter

“…To support this contention, we previously reported preliminary evidence for central serotonin-based anomalies in ASD 19 , including the functional response to facial expressions of emotion 8 . Specifically, using fMRI we discovered that lowering 5-HT levels in individuals with ASD using a tryptophan depletion protocol shifts the brain functional response to emotional faces towards a more neurotypical pattern 8 .…”

Oxytocin and serotonin in the modulation of neural function: Neurobiological underpinnings of autism-related behavior

“…So SSRI intervention to increase the serotonin in the synaptic cleft of autistic children should improve the stereotyped behavior and other ASD symptoms. Unfortunately, SSRI treatment has been reproted to be effective for adults, but it does not significantly improve the symptoms of autistic children and adolescents (Williams et al, 2013;Wichers et al, 2019). At present, it is not clear why this significant difference in therapeutic effect exists, and it may be related with the therapeutic dose of SSRI.…”