NAC for 'social impairment' in youth with autism... probably not

"The results of this trial indicate that NAC [N-acetylcysteine]  treatment was well tolerated, had the expected effect of boosting GSH [glutathione] production, but had no significant impact on social impairment in youth with ASD [autism spectrum disorder]."

So said the results reported by Logan Wink and colleagues [1] (open-access) who, continuing an autism research theme, looked at whether this important L-cysteine prodrug might have more to give when it comes to at least some facets of some autism. Their trial registration entry can be found here. Reporting results from "a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD" researchers followed some 30 children (aged 4-12 years) diagnosed with autism based on their use of NAC or a placebo. Alongside various biological measures including blood levels of "reduced and oxidized glutathione (GSH and GSSG)" and the big 'H' (homocysteine), the primary outcome was the effect on "the CGI-I scale anchored to study physician assessment of core social impairment considering the individuals’ overall level of cognitive, adaptive, and social functioning." I might add that other secondary behavioural outcomes were also included for study.

Bearing in mind the loss (dropping out) of some participants during the study period including details that "three withdrew due to irritability (NAC), diarrhea and encopresis (placebo), and defiant and self-injurious behavior (placebo), respectively" the authors report data on 25 study completers. Titrated doses of NAC depending on tolerance and body weight of participants did seem to do what they were supposed to in terms of an effect on levels of glutathione: "had the expected effect of boosting GSH production in peripheral blood" at 12 weeks.

But... on every other measure - biological and behavioural - there were no significant differences between the NAC and placebo groups leading the authors to conclude that their results "do not support the use of NAC for treatment of core social impairment of ASD." The research door does however remain open as they also comment that: "the health impact of the resultant increase on GSH remains unclear."

These are interesting results. NAC has seemingly found something of a research place in quite a few areas of psychiatry including 'some' autism (see here) and 'some' schizophrenia (see here). The focus has tended to be more on the 'irritability' side of things (see here) which makes it all the more surprising that one of the participants in the Wink trial receiving NAC actually withdrew 'due to irritability'. That being said, the very controlled nature of the Wink study cannot be readily ignored assuming no influence from the placebo [2].

I would like to see a little more on the whole NAC -- cysteine -- glutathione connection given previous discussions with autism in mind (see here). This includes the idea that blood levels of the various compounds involved might not be the same as 'brain levels' and taking into 'level of functioning' into account (see here). But in the context of the Wink data, one has to perhaps realise that NAC is not likely to be a panacea when it comes to autism...

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[1] Wink LK. et al. A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Molecular Autism. 2016; 7:26.

[2] Masi A. et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015 Sep 22;5:e640.

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Wink, L., Adams, R., Wang, Z., Klaunig, J., Plawecki, M., Posey, D., McDougle, C., & Erickson, C. (2016). A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder Molecular Autism, 7 (1) DOI: 10.1186/s13229-016-0088-6

Social anxiety in one in four adults with autism

"Twenty-eight percent (14 of 50) of individuals with ASD [autism spectrum disorder] fulfilled the diagnostic criteria for SAD [social anxiety disorder]".

"I am Vulcan, sir. We embrace technicality."

So said the findings reported by Susanne Bejerot and colleagues [1] (open-access) as part of their investigations looking at SAD occurrence among adults diagnosed with ASD. Once again the sometimes very disabling issue of anxiety resurfaces with autism in mind. Before going on, I'm minded to reiterate that SAD in the context of this research/post means social anxiety disorder and not seasonal affective disorder (which also uses the same acronym).

The Bejerot paper is open-access but a few factoids from the study might be in order:

• Drawing on participant data derived from another study by the authors [2] talking about [some] autism as potentially being representative of a "gender defiant disorder", 50 adults diagnosed with autism were compared with 53 asymptomatic controls and 100 participants diagnosed with SAD.
• Various measures were used to ascertain things like autistic traits and the presence of any other psychiatric issues including the Mini International Neuropsychiatric Interview (M.I.N.I.) and the Autism Spectrum Quotient (AQ). When it came to looking at social anxiety and social avoidance, the Liebowitz Social Anxiety Scale Self-Report (LSAS-SR) was used and "SAD diagnosis was established by diagnostic interview using the Structure Clinical Interview for DSM-IV (SCID)".
• Results: those diagnosed with SAD (not comorbid to autism) showed the highest (mean) scores when it came to social anxiety and avoidance based on the LSAS-SR measure. This is probably not an unexpected finding given that they were already diagnosed with SAD. But... the ASD group were not that far behind based on their scores on these parameters and ahead of the asymptomatic controls: "[significantly] higher scores of anxiety and avoidance in ASD relative to subjects in the non-ASD comparison group".
• Then the headline result suggesting that over a quarter of those with autism also fulfilled diagnostic criteria for SAD (based on their M.I.N.I results) and further that: "the 14 individuals that fulfilled the criteria for social anxiety had a higher AQ score... than the rest of the group". This last point potentially ties the two diagnoses (autism and SAD) together as per some recent chatter about intolerance of uncertainty and autism (see here) and with social communication issues specifically in mind, the findings reported by Georgia Halls and colleagues [3] (open-access).

There are some potentially very important points to take from the Bejerot findings specifically in relation to the requirement for further screening as and when a diagnosis of ASD is received. It's an all too common theme these days, that the label 'autism' rarely exists in a diagnostic vacuum both during childhood (see here) and into adulthood (see here for example). Although not exactly making great reading, some of that comorbidity (if that is what it actually is) can for some people on the autism spectrum, lead down some very dark roads indeed (see here). The first step it seems, is screening for said comorbidity in order to start thinking about how such issues can be mitigated and quality of life improved (as and when required).

Just before I leave you to further mull over the Bejerot findings, I'll also draw your attention to a few other details discussed by the authors. They talk about possible "differences in the quality of social anxiety in ASD and SAD" as a function of some of the unique issues which follow a diagnosis of autism. So, social awkwardness is discussed, and the quite sweeping statement that "the ASD group is socially awkward" as being a possible differentiator from the SAD group who: "sense that they are socially incompetent" despite possessing the appropriate skills to socialise. I assume this idea stems from the developmental aspect of autism?

Interestingly too, the authors also suggest that issues with the concept of insight might be something which may help protect some on the autism spectrum from developing social anxiety. The idea being that the realisation of said social awkwardness might promote social anxiety and conversely "individuals with ASD and poor insight may be protected from developing social anxiety". As difficult an issue this might be to think about, the authors draw on other data which proposed that: "either unawareness of, or perhaps being unconcerned with how people perceive them, could be protective factors for social anxiety [in cases of autism]". Certainly there seems to be quite a bit more to do in this area outside of other potentially important work [4]. I wonder also for example, whether the concept of self-monitoring might come into play here too?

Music to close and having seen Bryan Adams last evening, I have something of a new found admiration for some of his music, so here is a classic: Summer of '69.

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[1] Bejerot S. et al. Social anxiety in adult autism spectrum disorder. Psychiatry Research. 2014; 220: 705-707.

[2] Bejerot S. et al. The extreme male brain revisited: gender coherence in adults with autism spectrum disorder. Br J Psychiatr. 2012; 201: 116-23.

[3] Halls G. et al. Social communication deficits: Specific associations with Social Anxiety Disorder. Journal of Affective Disorders. 2015; 172: 38–42.

[4] White SW. et al. Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: understanding anxiety in autism spectrum disorder. Int J Dev Neurosci. 2014 Dec;39:22-36.

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Bejerot S, Eriksson JM, & Mörtberg E (2014). Social anxiety in adult autism spectrum disorder. Psychiatry research PMID: 25200187