Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a fail

"B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS [Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]."

That was the conclusion reached in the paper by Øystein Fluge and colleagues [1]. Their findings based on the use of rituximab, "a drug that is often used to treat inflammatory diseases (for example, rheumatoid arthritis) and lymphoma" were not entirely unexpected (see here) as a familiar theme of small scale results [2] being 'positive' but not translating into gains during more methodologically-sound study was rehashed.

The Fluge paper also has an accompanying easy-read summary of the results [3] which really aids my job. The long-and-short of it was that over 150 patients diagnosed with ME/CFS were enrolled into the study. Most had been ill with ME/CFS for several years. They were randomly assigned to receive either rituximab or saline (control) over the course of 1 year. Said timing and dosage of rituximab started with "2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months." Participants completed various 'self-reported' questionnaires about their fatigue and functioning over a 2-year period alongside some more objective measurement of physical activity. Results were collated, and well, there was very little difference between rituximab and saline use noted when comparisons were made. What was notable in the published findings were the quite high rates of side-effects observed: "Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events" and over a third of those adverse events were considered 'possibly or probably related to' rituximab use.

What's more to say? Well, the discrepancy between these latest findings and other previous results suggests a couple of potentially important processes *might* be at work. First, the placebo response seems to be quite prominent in this patient group. I say that on the basis that the calculated placebo response among those receiving saline ranged between 25-50% across the various centres that recruited participants for this study. Other commentators (see here) have similarly mentioned how the placebo response seems to be typically quite high in ME/CFS, and how that might have also been on show in other studies too (see here). This could have lots and lots of implications for various intervention trials relevant to ME/CFS. Second, one has to consider that similar to various other labels that include some significant heterogeneity 'under them', there may be responders and non-responders [4] to consider in relation to the use of something like rituximab [5]. Third, and also quite important is to mention that although negative, these results don't invalidate the idea that immune function seems to have something of an important relationship with quite a few cases of ME/CFS (see here for example).

Having said all that, it is difficult to talk about further research on rituximab with ME/CFS in mind on the basis of the Fluge negative results. Not least because, like all medicines, there is a risk-benefit balance to be struck with such a preparation and failures using gold-standard experimental methodologies cannot be easily brushed under the scientific carpet...

----------

[1] Fluge Ø. et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2019. April 2.

[2] Fluge Ø. & Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28.

[3] Patient Summary: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Annals of Internal Medicine. 2019. April 2.

[4] Rekeland IG. et al. Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9.

[5] Morris MC. et al. Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clin Ther. 2019 Mar 28. pii: S0149-2918(19)30112-2.

----------

Video Interaction for Promoting Positive Parenting in autism: yes but not quite...

"Video feedback may help babies ‘at risk of autism’" went one write-up of the study results published by Jonathan Green and colleagues [1] (open-access available here). Continuing a theme of kids at risk of autism potentially 'avoiding' an autism diagnosis (see here) following the use of "a 12-session parent-mediated social communication intervention delivered between 9 and 14 months of age (Intervention in the British Autism Study of Infant Siblings-Video Interaction for Promoting Positive Parenting)" there is some degree of optimism from these latest results together with a pinch of 'not-so-fast'...

Including data from some 54 families - "28 intervention, 26 nonintervention" - researchers reported on the effects of interventions vs. no intervention on various aspects of functioning primarily the "severity of autism prodromal symptoms." Prodromal means early symptoms and is more readily associated with other labels/conditions. The authors reported that results were not completely cut-and-dried in terms of effect(s) of intervention on diagnostic outcome for example (i.e. there were "no intervention effects on diagnostic outcome") but potentially something to see when it comes to the 'severity' of autism prodromal symptoms and "parent-dyad social communication." The authors also noted that measures of communication and language did show something of a trend towards some benefit observed in the intervention group, but did not yield any significant difference when comparing intervention with no intervention over the quite long study period (39 months). This contrasts with their previous results [2] possibly indicating something rather more adverse when it came to intervention and aspects of language/communication. I might also draw your attention to the fact that from a bank of some 84 families invited to join the study, just over half actually agreed or fulfilled the criteria for joining.

I know this is an area of research that people really want to see work. Alongside other early intervention research in relation to autism (see here for example), the idea that some small adjustments to early interactions might affect the presentation of autism still enjoys quite a lot of support in various quarters. The thing is that these and other results whilst suggesting that things like 'parental responsiveness' can improve as a result of intervention(s), have so far shown that important outcomes for young children are far less impressive. This is something evident across quite a lot of the research literature in this area even when meta-analysed (see here including some chatter about effect sizes).

I'm not suggesting that we everyone just 'gives up' when it comes to early interventions like the one described by Green and colleagues. I do however think science and clinical practice needs to be a little more focused on things like potential best-responders to such interventions (as it does for many other aspects of autism science) and not so focused on creating grand media headlines. I might also throw in the idea that study design is something that needs to be improved particularly in light of other recent findings [3] talking about how "placebo-like effects represent substantial challenges for randomized controlled trials (RCTs) that use treatment as usual" (guess what many studies in this area use as their comparator?) Accepting that variables such as the plural autisms (see here) are inevitably going to affect results from such studies, I'm minded to suggest that quite a few more resources need to be committed to looking at the possible 'hows and whys' of autism coming about before any talk about early parent-mediated intervention becoming widespread. So, questions like whether screening for inborn errors of metabolism in relation to autism (see here) could be a good first step as part of the mantra 'diagnosis is a starting point not the finishing line' and then taking things from there...

----------

[1] Green J. et al. Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. J Child Psychol Psychiatry. 2017 Apr 10.

[2] Green J. et al. Parent-mediated intervention versus no intervention for infants at high risk of autism: a parallel, single-blind, randomised trial. Lancet Psychiatry. 2015. Jan 22.

[3] Jones RM. et al. Placebo-like response in absence of treatment in children with Autism. Autism Res. 2017. 12 April.

----------

Green J, Pickles A, Pasco G, Bedford R, Wan MW, Elsabbagh M, Slonims V, Gliga T, Jones EJ, Cheung CH, Charman T, Johnson MH, & British Autism Study of Infant Siblings (BASIS) Team. (2017). Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. Journal of child psychology and psychiatry, and allied disciplines PMID: 28393350

Vitamin D supplementation and self-perceived fatigue

"Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency."

Supplementation details, described in the paper by Albina Nowak and colleagues [1] (open-access available here), were a single dose of 100,000 IU [international units] of vitamin D or a placebo (mannitol) administered to 120 adult participants who presented with "fatigue and vitamin D deficiency (serum 25(OH)D < 20 μg/L)." This was a double-blind trial and self-perceived fatigue was measured using the fatigue assessment scale (FAS) at baseline (before intervention) and after 4 weeks.

This is an interesting paper but not without some issues. Use of the FAS is OK but I would have preferred to see something else accompanying the data derived from this schedule when it comes to something like self-reported fatigue. The authors did rely on a "short self-developed fatigue test (fatigue course assessment; FCA)" too during their study but I was thinking of something a little more standardised. Although data for some 120 participants were available for the study results , I was a little surprised to see that some 280 participants were initially screened for study inclusion; most of whom did not make the cut. The vast majority (n=103) were cut because "25-OH vitamin D levels >20 μg/L" or in other words, they were not classified as vitamin D deficient based on analysis by immunoassay. Bearing in mind the idea that deficiency is not the only categorisation when it comes to vitamin D and not everyone agrees where deficiency actually starts and stops, I'd perhaps have liked to have seen some more information about those excluded, particularly those on the periphery of being classified as deficient and what supplementation might have meant for them.

It's also interesting to see the strength of the placebo effect when it came to the study results as alongside the 70%+ who reported "amelioration" of fatigue who were actually in receipt of vitamin D, so half of the placebo group also registered the same/similar improvement. As far as I know mannitol is not known as a fatigue reducing agent so there's potentially something more going on here. "A significant increase in 25-OH vitamin D was observed in vitamin D but not in placebo-treated participants." Given the supplementation of vitamin D at such a high dose it's perhaps not surprising that vitamin D levels went up for those consuming the supplement.

The Nowak results do stand, and even though they were based on self-reported fatigue in an otherwise healthy cohort, I do wonder whether there may be some tie-ups with other independent study (see here for example). Accepting that there may be many reasons for fatigue, I'm also inclined to point out that for perhaps at least a subset of those diagnosed with something like chronic fatigue [syndrome], there could be some additional studies to undertake bearing in mind the authors assertion that: "our study results are not generalizable to CFS [chronic fatigue syndrome]."

To close, what if ‘There's Something About Mary’ was trailed as a Psychological Thriller?

----------

[1] Nowak A. et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). 2016 Dec;95(52):e5353.

----------

Nowak A, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, Bischoff-Ferrari HA, Suter PM, & Krayenbuehl PA (2016). Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine, 95 (52) PMID: 28033244

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...

----------

[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.

----------

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

Gluten- and casein-free diets and autism: the Hyman results (at last)

"Although these findings must be interpreted with caution because of the small sample size, the study does not provide evidence to support general use of the GFCF [gluten-free/casein-free] diet."

So said the results of the study finally published by Susan Hyman and colleagues [1] detailing the effects (or not) of a small (n=14) "double-blind, placebo-controlled challenge study" of the use of a diet devoid of gluten and casein for young children diagnosed with an autism spectrum disorder (ASD). If you really want some background history to this often controversial area of autism research, look no further than some of my past musings on this blog (see here and see here) or if you wish, in peer-reviewed form [2].

I say 'finally' in that previous sentence about publication because there has been a considerable degree of waiting for these results to appear in complete peer-reviewed form given that the trial was initially registered in 2004 and things were all supposed to have been wrapped up in 2009 (see here for the ClinicalTrials.gov entry). Some people with their eyes and ears to the autism research grapevine will have probably heard about some of the whys and wherefores of the delay in publishing these results, but I'm not going to get too involved in that here.

Unfortunately the paper is not open-access at the present time but I'll give you a summary of some of the mechanics and findings:

• Some 66 children were initially assessed for eligibility. This was whittled down to 22 kids taking into account those who declined to participate and those who "did not meet inclusion criteria." That inclusion criteria by the way "required children to be enrolled in a comprehensive applied behavior analysis (ABA) intervention program from one of two community agencies" as well as excluding those where seizures were part of clinical presentation and/or the "presence of a chronic illness in addition to ASD that required medical management, celiac disease, documented food allergy to wheat or milk, nutritional compromise such as iron deficiency that required treatment, and family inability to complete rating scales and assessments in English."
• The study design was interesting. It included an implementation phase whereby a GFCF was put in place over the course of 2 weeks (baseline) and maintained for at least 4 weeks. Then came the challenge phase which consisted of weekly challenges to the diet for 12 weeks including one of the following: "foods that contained gluten only, casein only, both gluten and casein, or neither (placebo)." Finally, there was a maintenance period where families were free to "maintain, modify, or abandon the GFCF diet in this phase."
• Various assessments were carried out throughout the study phases covering areas of "physiologic functioning, challenging behaviors (not specific to ASD), and behaviors associated with ASD."
• Results: well, data for 14 of the 22 children were analysed as a function of attrition and or other factors such as "laboratory exclusion criteria." First and foremost we are told: "No serious adverse events were reported during the trial." First, do no harm and all that. When looking at sleep quality and quantity, stool frequency and type, a measure of ADHD (attention-deficit hyperactivity disorder) and a measure of behaviours associated with autism (the Ritvo-Freeman Real Life Rating Scales), authors reported no significant effect following dietary challenges. In other words: "experimental challenges [to the GFCF diet] were not reliably associated with more frequent ASD behaviors." That being said: "All of the families elected to continue the diet for the 12 weeks after completion of the challenges."
• There are some significant strengths to this data based on close monitoring of adherence to the diet, controlling the consumption of gluten and casein levels in challenge snacks and the use of ABA in terms of "stable, consistent educational and behavioral services."
• Likewise however, there are some notable issues associated with the study and the findings outside of the small participant group, not least the emphasis on 'dietary challenge' and importantly the fact that researchers "excluded children who had known gastrointestinal disorders, who might have been more likely to respond positively to dietary restriction." This last point ties in well with other literature in this area [3]. I might add that "individualized supplementation was added for a few participants when deemed necessary by the study dietitian to address low intake of iron, calcium, or vitamin D." Interesting (see here).
• The authors conclude that their study "does not provide evidence to support general use of the GFCF diet" with caveats. 

I can imagine that the Hyman results are probably going to generate some interesting discussions depending on your view of a GFCF diet for autism. I have a professional interest in this topic given some of my research history in this small part of the autism research arena [4] but have tried to stay as objective as possible as per other entries on this topic (see here).

Despite any potential bias I might have, I do still think there is more to see in this area of diet and autism. I've talked before about the idea that the diagnosis of autism is by no means protective against other conditions/labels appearing including those related to issues with gluten for example (see here). This similarly applied to milk also (see here). Some of other peer-reviewed research that I've also been a part of has hinted that there may be 'best responders' to this type of intervention [5] (see here for more discussion); something which ties in well with the concept of plurality and autism (see here).

That caveat about the Hyman study excluding children with known gastrointestinal (GI) disease is also worth re-iterating. Again, this takes autism research into some controversial areas (see here) but as per recent data, both functional (see here) and pathological bowel disorders (see here) do seem to over-represented in cases of autism, so one might see this as an area ripe for further dietary investigations. Indeed, one assumes we might see if there is anything in such an association as and when the Harland Winter trial sees the peer-reviewed light of day (hopefully quite soon).

----------

[1] Hyman SL. et al. The Gluten-Free/Casein-Free Diet: A Double-Blind Challenge Trial in Children with Autism. Journal of Autism and Developmental Disorders. 2015. Sept 5.

[2] Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013 Jan 4;6:344.

[3] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

[4] Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

[5] Pedersen L. et al. Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: behavioural and psychometric measures of dietary response. Nutr Neurosci. 2014 Sep;17(5):207-13.

----------

Hyman, S., Stewart, P., Foley, J., Cain, U., Peck, R., Morris, D., Wang, H., & Smith, T. (2015). The Gluten-Free/Casein-Free Diet: A Double-Blind Challenge Trial in Children with Autism Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-015-2564-9

No really, it's a placebo...

An entry on ScienceDaily titled: 'Turning fake pills into real treatments' caught my eye recently and with it a link to one of the most famous placebo experiments by Ted Kaptchuk and colleagues [1] (open-access here).

In the 2010 paper, Kaptchuk et al reported that even when told a placebo - a substance that has no therapeutic effect - is a placebo, when compared to a no-treatment option, participants diagnosed with irritable bowel syndrome as a group reported greater improvements in their symptoms. As per the authors' comments: "results challenge “the conventional wisdom” that placebo effects require “intentional ignorance.”"

I don't mind telling you that I find this area of science to be absolutely fascinating. The placebo effect classically delivered with deception (also ideally including various information: a pill branded by a well-known pharmaceutical company, perceived as an expensive treatment accompanied by positive information from someone perceived to be a doctor and wearing a white coat) is intriguing enough but potentially even showing effects even when known to be a placebo?

Granted the non-deceptive placebo response is probably not going to be generalisable across all patient groups and all conditions as per other work including Kaptchuk on the authorship list [2]. But this line of research does perhaps require quite a bit more systematic evaluation as to who might be 'best responders' and whether science can identify such people via investigations of the 'placebome' for example [3]. With the rise and rise of the science of epigenetics, one also wonders whether there may be something complementary to see there too minus any hype.

Given the reliance on placebo near the top of the hierarchy of science - the placebo-controlled study - one might also reasonably ask the question as to what extent our growing knowledge of the placebo response might be affecting the quality of some of our science and what we can do about it. I'll draw your attention to a paper I have discussed before on this blog by Samokhvalov and colleagues [3] and their suggestion that: "naltrexone, upon further investigation, might be used in randomised clinical trials in addition to or as an alternative to a placebo." I'm a follower of naltrexone research on this blog (see here). Added to the possible ways and means that trial design might be adapted as per the suggestion from Sylvain Chassang and colleagues [4] and the concept of 'high' and 'low' probability of treatment being added into the statistical mix, and the Kaptchuk findings prove their worth not just when it comes to the potential effects of placebo...

Music: The Doors - Riders On the Storm.

----------

[1] Kaptchuk TJ. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One. 2010 Dec 22;5(12):e15591.

[2] Kelley JM. et al. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom. 2012;81(5):312-4.

[3] Samokhvalov AV. et al. Naltrexone may block euphoria-like placebo effect. BMJ Case Rep. 2013 Aug 7;2013.

[4] Chassang S. et al. Accounting for Behavior in Treatment Effects: New Applications for Blind Trials. PLoS One. 2015 Jun 10;10(6):e0127227.

----------

Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, Kowalczykowski M, Miller FG, Kirsch I, & Lembo AJ (2010). Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS one, 5 (12) PMID: 21203519

Efficacy of foetal stem cell transplantation in autism...

The recent news that researchers might be one step closer to 'curing' type 1 diabetes following the publication of the paper by Pagliuca and colleagues [1] brought back into focus how stem cell therapy might hold some promise for all manner of conditions. The idea that researchers could generate "hundreds of millions of glucose-responsive β cells from hPSC [human pluripotent stem cells] in vitro" still faces a few challenges, including overcoming the immune assault central to the autoimmune condition that is type 1 diabetes. I have but one comment to make about the immune system and autoimmunity in this context: worm pills (see here)...

The question of whether an advance has been similarly made following the publication of the paper by Jeff Bradstreet and colleagues [2] (open-access available here) is perhaps open to some discussion with their observations that: "Statistically significant differences (p<0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory and overall health, as well as reductions in the total scores when compared to pre-treatment values" based on the use of foetal stem cells (FSCs) "in treating children diagnosed with ASDs [autism spectrum disorders]". Further details about the study can also be found in the latter slides of the presentation shown here.

Stem cell therapy in the context of autism is still a scientific hot potato. I've covered previous, very preliminary, forays into this research area before on this blog (see here). It is with the same cautions and caveats that I discuss the latest paper from Bradstreet et al.

So:

• This was a study of some 45 children diagnosed with an autism spectrum disorder (ASD) (mean age = 6-7 years). Diagnosis was confirmed by some of the gold-standard assessment instruments including ADOS and ADI. There were quite a few exclusion criteria applied to study entrants such that those with epilepsy, or "a neurological or co-morbid psychiatric disorder" were not examined. Learning disability without autism was also "considered exclusion criteria" as was a diagnosis of Asperger syndrome.
• The study was based in Kiev in the Ukraine where "stem cells harvested from 5-9 weeks old human fetuses following voluntarily – elective pregnancy terminations (legally available in the Ukraine)" were used. I don't doubt that there may be some who have strong views about this practice as per commentary from other authors (see here). Hematopoietic stem cells (HSCs) after harvesting were tested for various bacterial, fungal and viral infections as were the women who previously carried.
• Long quote coming up... "Stem cell transplantation of suspensions containing cryopreserved fetal stem cells were preceded by pre-medication of the subject via intravenous slow infusion of diphenylhydramine (Darnitsa, Ukraine) 10 mg and prednisone (Darnitsa, Ukraine) 15 mg on Day 1 and diphenhydramine (Darnitsa, Ukraine) 10 mg on Day 2". At this point, I'll draw your attention to some other work previously discussed on this blog on a possible role for corticosteroid therapy for some types of autism (see here) which included the use of prednisolone, the active metabolite of prednisone. After which the stem cells were administered...
• Results: "Early post-transplantation effects were reported in 78% of children: 26% of these children became calmer; eye contact was improved in 9%, while 29% had better appetite and 23% had an improved affect". Importantly, the authors report that no adverse effects were initially noted and "No transmittable diseases were noted during the 12 month follow-up". They also make mention of how initial effects may well have been [partly] as a consequence of the corticosteroid and other medication initially administered.
• Scores on the ATEC and ABC bore out the positive group changes noted between baseline (before stem cell therapy) and at 6 and 12 month follow-up which were also accompanied by various immunological changes "indicative of improved cell-mediated immunity in children".

OK. Despite these results the authors themselves are still cautious about their findings and stress: "future research studies are urgently needed and larger randomized -placebo controlled trials are needed to further characterize potential FSC-associated improvements in ASDs". This was a straight forward observational trial (before and after) which lacked control groups and in particular a placebo-controlled element so one has to be slightly hesitant about the strength of any findings. For those however who might be pulling on this study because of the use of something like the ATEC to measure autistic presentation, I'll draw your attention to some work suggesting that this instrument might be rather useful for monitoring intervention options for autism (see here).

As previously described, feelings run deep about the use or not of stem cells when it comes to autism not least because of the lack of data on long-term safety (and efficacy) in this context, the source 'material' for stem cells and the lack of information on just what might be going on in biological terms consequent to the behavioural results described. Examining this research from a cold, dispassionate, scientific point of view, I have to say that I'm becoming rather interested in what might be potentially going on during this and other studies [3] if not just as a function of other work by the late Paul Patterson and colleagues overlapping with this area [4] (discussed in a previous post). 

That being said, I'd like to see a lot more research done in this area before this kind of intervention enters anything like mainstream autism practice...

----------

[1] Pagliuca FW. et al. Generation of Functional Human Pancreatic β Cells In Vitro. Cell. 2014 Oct 9;159(2):428-439.

[2] Bradstreet JJ. et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014 Oct 9.

[3] Lv YT. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013 Aug 27;11:196.

[4] Hsiao EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81.

----------

Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, & Siniscalco D (2014). Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell transplantation PMID: 25302490

New life for naltrexone and autism?

During the very earliest days of the life of this blog I posted about the opiate antagonist naltrexone (ReVia®) and some research on its history with autism in mind; in particular, the various emerging speculations on low dose naltrexone (LDN) (see here). Today I'm following up that entry based on the results of a systematic review by Ashok Roy and colleagues [1] on the value (or not) of naltrexone for "attenuating the core symptoms of autism spectrum conditions in children".

"Yadwigha in a beautiful dream" @ Wikipedia 

The authors report: "Naltrexone may improve hyperactivity and restlessness in children with autism but there was not sufficient evidence that it had an impact on core features of autism in majority of the participants. It is likely that a subgroup of children with autism and abnormal endorphin levels may respond to naltrexone and identifying the characteristics of these children must become a priority".

I am not unhappy with this statement. Realising that autism is probably better represented by the plural 'autisms' and, as with just about every intervention put forward for the autisms, there is not one-size-fits-all measure, it makes good sense to seek out those best- and non-responders to something like naltrexone therapy. The fact that the authors also talk about "abnormal endorphin levels" as potentially being one guide for responder status harks back to the work of Gillberg and colleagues [2] from decades ago. I've also talked before about how other interventions such as the use of a gluten- and casein-free (GFCF) diet (which may very well be related to any naltrexone effect) seem to also affect more peripheral functions over core behaviours when it comes to autism (see here).

As odd as it might sound that a drug more normally used for the management of opioid dependence or alcohol dependence should potentially affect the presentation of at least some autism, there is perhaps some logic to its use. Opioid, by the way, refers to drugs such as morphine and codeine which bind to the opioid receptors we all have and produce various effects, most famously analgesia (pain relief) or in the case of abuse of such drugs, euphoria (happiness and wellbeing) at least for a short time. Naltrexone and other opioid antagonists produce an effect by blocking those opioid receptors, such that opioids cannot bind to them and so don't carry their prescribed effects. This similarly applies to our own internal opioid system including the endorphins. This euphoria blocking effect has also been put forward as a possible counteraction to the placebo effect too [3].

Of course one has to accept that one of three potential scenarios may be related to autism if one is to believe that naltrexone might seriously affect the presentation of symptoms for some:

1. that autism, some autism or its comorbidity, may have an element of opioid involvement to underlying biochemistry as per the Gillberg endorphin findings or even speculations that something like the opioid-excess hypothesis [4] may show involvement to cases, bringing in the GFCF diet angle. I hasten to add that I am not insinuating that autism is due to opioid addiction or anything like that.
2. that some autism may have an element of immune system involvement in light of the proposed action of something like LDN on inflammatory processes [5] and the preliminary signs of an effect on some cases of inflammatory bowel diseases such as Crohns disease [6] which might yet be relevant to other autism research (see here).
3. that any effect is purely epiphenomenal; just coincidence or a placebo effect, bearing in mind the Samokhvalov paper [3].

I'm not on this occasion going to offer any particular opinion about those options. I'd like to think that scenarios 1 and 2 are the more likely options in light of some [limited] results under double-blind, placebo-controlled conditions [7] for naltrexone acting on autism, but echoing the sentiments of Roy et al, there is much more investigation required in this area.

I do find the topic of naltrexone and autism to be a particularly interesting area of research. As also mentioned in a previous post on drug refractory aggression and autism, naltrexone continues to find favour for aiding some people on the autism spectrum, with the promise of so much more. You will be hearing more from me on this topic in future, particularly on some of our own research which has just cleared the peer-reviewed hurdle with drug delivery methods in mind...

Now, some music to liven things up... AC/DC and a very famous guitar riff...

---------

[1] Roy A. et al. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. J Intellect Disabil Res. 2014 Mar 4.

[2] Gillberg C. et al. Endorphin activity in childhood psychosis. Spinal fluid levels in 24 cases. Arch Gen Psychiatry. 1985 Aug;42(8):780-3.

[3] Samokhvalov AV. et al. Naltrexone may block euphoria-like placebo effect. BMJ Case Rep. 2013 Aug 7;2013. pii: bcr2013010098. 

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Younger J. et al. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014 Feb 15. 

[6] Segal D. et al. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2014 Feb 21;2:CD010410.

[7] Willemsen-Swinkels SH. et al. The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Biol Psychiatry. 1996 Jun 15;39(12):1023-31.

----------

Roy A, Roy M, Deb S, Unwin G, & Roy A (2014). Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. Journal of intellectual disability research : JIDR PMID: 24589346

Bumetanide for autism?

The paper by Lemonnier and colleagues* (open-access) reporting results from a randomised, placebo-controlled trial of the diuretic drug bumetanide in cases of autism has received quite a bit of publicity over the past few days. As with other big autism research news, the study was accompanied by quite a good write-up in Nature (see here) which very conveniently allows me to skip over the ins and outs of the study and pick out a few notable points in this brief post.

As always with the 'no medical advice given' caveat in full working order:

• This was a gold-standard trial insofar as similar to other research discussed on this blog it was randomised and also incorporated a placebo into the methodology which meant that participants were randomly assigned to treatment or not and the 'not' consisted of something that I assume, looked, smelled and tasted the same as bumetanide. Indeed the study lists 'lactose' as being the placebo which is fine as long as participants with autism did not have a lactose intolerance as per other autism research findings.
• Bumetanide as well as being a diuretic (increasing urine excretion) is a loop diuretic acting on a specific part of the kidney. Its uses are varied but mainly focus on reducing swelling and fluid retention following problems with the heart and other organs. It's also apparently quite good for treating hypertension (high blood pressure) too** and potentially useful for certain types of epilepsy*** (although I'd like to see more data on this effect). 
• Quite a lot of the focus on why the drug seemed to affect autistic behaviours has been on the GABA side of things and how "disruption of GABA is due to increased levels of chloride ions in the brain cells" in case of autism. The theory goes that bumetanide has an effect of decreasing levels of chloride in neuronal cells, which theoretically should positively alter that GABA disruption. In particular is the proposed action of bumetanide on NKCC1 an importer of chloride, where if I understand it correctly, bumetanide blocks NKCC1 from doing its duties. Indeed I might be confusing myself even further but NKCC1 also has something of a relationship with hypertension****.
• Why am I focusing on the hypertension side of things? Well, with all that we think we know about autism in terms of stress responses and comorbidity potentially focused on things like hypertension***** as part of the whole metabolic syndrome side of things, one might also be minded to look at whether this might have been part and parcel of any effect noted. Of course, I'm just speculating, bearing in mind that no measure of blood pressure for example, was seemingly reported during the trial. 
• As per this review by Ward & Heel****** (open-access), there are several other physiological changes/effects associated with taking bumetanide, all of which should remain at the back of one's mind when thinking about potential mechanisms of effect.  

I've not got too much more to say about this work aside from it being quite an interesting study and indeed (a) providing further support for how the myriad of pharmaceutical compounds we use might have many more uses than those cited on the patient information leaflet, and (b) how some of the effects of such medicines in cases of autism might be more evidence for the 'whole-body' nature of the condition, or at least some cases of the condition.

'Nuff said.

[Update: February 2014. Well it wasn't exactly 'nuff said as indeed, more was subsequently said on this topic... see this post on bumetanide, GABA, oxytocin and mouse models of autism].

----------

* Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry. 2012: e202.

** van der Heijden et al. A randomized, placebo-controlled study of loop diuretics in patients with essential hypertension: the bumetanide and furosemide on lipid profile (BUFUL) clinical study report. J Clin Pharmacol. 1998; 38: 630-635.

*** Eftekhari S. et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia. October 2012.

**** Ye ZY. et al. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci. 2012; 32: 8560-8568.

***** Tyler CV. et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. 2011; 116: 371-380.

****** Ward A. & Heel RC. Bumetanide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs. 1984; 28: 426-464.

----------

Lemonnier, E., Degrez, C., Phelep, M., Tyzio, R., Josse, F., Grandgeorge, M., Hadjikhani, N., & Ben-Ari, Y. (2012). A randomised controlled trial of bumetanide in the treatment of autism in children Translational Psychiatry, 2 (12) DOI: 10.1038/tp.2012.124

The placebo effect

This post probably best falls into my other musings description of this blog. Don't however assume that it does not tie into autism or other developmental conditions though, as will hopefully be revealed.

Placebo, aside from being a band, refers to a sham intervention, normally medical, provided during an intervention study. Normally just a sugar pill or some other similarly innocuous substance or intervention, the placebo is designed to act as a control, a standard against which a proposed efficacious compound or substance or intervention is tested. To boil it down, it works something like this:

• Compound A is a proposed treatment for condition X. Compound A is made into a tablet or something similar and submitted for experimental testing. 
• Compound B is a placebo with no claim or connection to condition X. It is also formulated into a tablet exactly the same as compound A in appearance, smell, taste, etc. 
• During an experimental trial, patients are, without knowledge of which, either allocated compound A (experimental treatment) or compound B (placebo). 
• The effects of compounds A and B are compared. 
• Should compound A show some effect for condition X, one would expect significantly better results compared with compound B, the placebo.

There are various other ways of using a placebo during such experimental study (the cross-over study, comparing more than one treatment option). You can perhaps see how placebo should provide a gold-standard for such trials and how confidence should be high from any changes obtained against placebo. Simple. Well, not quite...

One of the possible side effects of using a placebo is the so-called placebo effect, whereby a proportion of participants given a placebo actually report an improvement in their symptoms. A recent paper illustrating the placebo effect in action is this one comparing St. John's wort, an anti-depressant and a placebo in the treatment of mild depression. The results of the study by Rapaport and colleagues not only suggested that SJW and citalopram could not be separated by significance as the best treatment course for mild depression, but that a placebo, a sham intervention, a sugar pill, actually improved some of the symptoms of mild depression at a rate similar to that found in the more recognised treatment modalities.

Similar results from the placebo effect have been reported with regards to pain management, hypertension, asthma and even Parkinson's disease.  Little wonder that the humble placebo has been touted as a potential treatment option for various things (not that I am recommending this option).

The question of how and why the placebo effect works is a little more challenging. There is a strong case for some brain-related changes following invokation of the placebo response. Having said that the precise areas involved (note the plural areas) remain under investigation. Mind over matter probably plays a hand, or at least the effects that a little knowledge and social expectation might bestow on reported health. Apparently the ideal placebo effect involves giving more than one placebo (two pills), branded by a well-known pharmaceutical company on the pill, for the treatment to be perceived as expensive, accompanied by information and direction, from a doctor wearing a white coat, on their proposed positive effects.

How does this all tie into autism?

Placebos have been used quite extensively as part of autism research. My post a few days back on the use of levocarnitine is a good example of placebo in action. With regards to the placebo effect in relation to autism, the information base is slightly lacking. Lisa Jo Rudy discussed the placebo effect in relation to autism in a post a few years back. As she pointed out, the placebo effect might be attenuated by lots of different factors such as age, and certainly might not be as strong in younger children with autism as older children as a result of differences in things like experience and expectation. I have to say that age independent of autism is still under investigation when it comes to the placebo effect. This meta-analysis of drug resistant epilepsy suggested that the placebo effect was actually magnified in children compared to adults.

I do wonder how such age differences might manifest themselves in relation to a developmental condition like autism. So, is any placebo effect moderated by cognitive-intellectual development or social development? Would any placebo effect be moderated by the presence of comorbid learning disability? Interestingly I have not been able to find very much looking experimentally at such issues. Assuming that there is a social aspect to the placebo effect ("this pill will reduce your symptoms"), young adults with high-functioning autism, are at least as likely as non-autistic controls to act on social cues as illustrated by this small study on magic and sleight of hand. So conceivably the placebo effect might be as strong in autism as that seen in not autism?

There are quite a few philosophical issues raised by the placebo effect. Placebo used as part of our yearning for an evidence-based medicine society is an important concept. Similarly however, one could question how much the placebo effect 'interferes' with results and could potentially lead to errors in our judgement of what does and does not provide potentially efficacious results.