Pioglitazone for autism?

Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass index] did not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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An inflammatory autism subtype?

The paper from Harumi Jyonouchi and colleagues [1] (open-access) continues a theme from this author with their suggestion of "an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by ‘flare’ ASD-IS [autism spectrum disorder - inflammatory subtype] monocytes".

Panic on the streets of Birmingham...

'Flare' ASD-IS in this case refers to a coding given to a small participant group (n=24) who were: "defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection)" and who experienced: "worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults)".

Innate immune system functions (yes, cytokines again) were measured in flare ASD-IS and compared with results from other groups: (i) controls with autism with a history of "non-IgE mediated food allergy (NFA)" (n=20), (ii) ASD/non-NFA controls (n=20), and (iii) "three groups of non-ASD controls (non-ASD/NFA subjects (N =16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N =18), and normal controls without NFA or PANS (N =16))". For those unfamiliar with the term PANS - pediatric acute onset-neuropsychiatric syndrome - this is a term originating from PANDAS (see here) and denotes an important condition bridging the link between infection and psychiatric symptomatology [2]. As if you needed telling...

Authors concluded that: "‘Flare’ ASD-IS PB Mo [peripheral blood monocytes] produced higher amounts of inflammatory cytokines (IL-1β and IL-6) without stimuli than ‘non-flare’ ASD-IS cells". They concluded that their findings: "support parental impression of worsening behavioral symptoms in the ‘flare’ state following immune insults" on the basis of the immune findings also linking in with behavioural descriptions at the time of sample collections.

Whilst including relatively small participant groups, it is the spread of presentations (not just based on diagnosis) which makes this paper stand out. I note that the authors also report that their results may: "indicate a possibility that monocytes from ASD-IS children also have intrinsic defects in regulatory mechanisms of IL-10 production". This is again, potentially important. Although there is still some misconception that cytokines are binary in function (either pro-inflammatory or anti-inflammatory) when the emerging data are suggesting it is very much more complicated than that (see here), the authors are hinting that inflammation with regards to autism may actually be down to issues with the opposing anti-inflammatory response over and above an upregulated pro-inflammatory response. Sort of like a fire tender not carrying enough water to put out a blaze. Indeed, work from this research team had previously hinted as much [3] (see also my previous post on this paper) as have other studies [4].

I am looking forward to seeing this research independently followed-up and reported on to further characterise those people with autism who such results are potentially relevant to. Whether gastrointestinal (GI) symptoms and dietary intervention might also be important factors [5] in such immune responses, also offers some potentially tantalising options for intervention...

Music to close: Rhapsody In Blue.

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[1] Jyonouchi H. et al. Cytokine profiles byperipheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an
inflammatory subtype? Journal of Neuroinflammation. 2014, 11:187

[2] Chang K. et al. Clinical Evaluation of Youth with Pediatric Acute Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2014 Oct 17.

[3] Jyonouchi H. et al. Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study. J Neuroinflammation. 2012 Jan 7;9:4.

[4] Estes ML. & McAllister AK. Alterations in Immune Cells and Mediators in the Brain: It's Not Always Neuroinflammation! Brain Pathol. 2014 Nov;24(6):623-30.

[5] Jyonouchi H. et al. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

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Jyonouchi H, Geng L, & Davidow AL (2014). Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype? Journal of neuroinflammation, 11 (1) PMID: 25344730