Carnitine supplementation and autism: "side-effects and behavioral outcomes"

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

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[1] Goin-Kochel RP. et al. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Global Pediatric Health. 2019; 6: 1-8.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011 Jun;17(6):PI15-23.

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Sulforaphane and autism continued: metabolomics wades in...

"We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism."

So said the findings reported by Stephen Bent and colleagues [1] continuing a theme in autism research circles examining the use of a compound called sulforaphane - "a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds" - in the context of [some] autism (see here). Once again, I'm sure that there may be people out there with brows furrowing when it comes to talk of a 'broccoli chemical' potentially impacting on the presentation of autism. But peer-reviewed science (placebo-controlled) is peer-reviewed science [2] and not just to be 'put to one side' because it doesn't follow the trends or [research] fashions of the day.

This latest work from Bent et al represents a not-so-methodologically strong attempt (i.e. not placebo-controlled) to bring the science of metabolomics into research proceedings to "examine changes in physiological markers that may underlie beneficial treatment effects from sulforaphane by analyzing changes in urinary metabolites." Metabolomics by the way, as well as being music to my research ears, is something that percolates through quite a lot of autism research these days (see here and see here for examples) as small molecules in urine, blood and other biofluids are separated, detected and elucidated all in the name of science.

A small group of children participated in the Bent study; all had a "formal diagnosis of autism", all were reasonably happy to swallow a tablet containing sulforaphane ("weight-based dosing of sulforaphane") and all were able to provide urine samples before the study started and at the conclusion of the 12 week research period. Parents of participants were also willing and able to complete a couple of behavioural schedules: "the Aberrant Behavior Checklist (ABC) and... the Social Responsiveness Scale (SRS)" at "baseline, 4 weeks, and 12 weeks using an online and secure platform" about their children too.

Results: alongside looking at pre- and post-intervention behavioural scores, the authors also "examined the number of participants who had a clinical response." This is a particularly important detail in the context of autism and the continuing discussions about how the spectrum is well and truly heterogeneous (the autisms?) and so one shouldn't expect every single person diagnosed to somehow have the same genetics and/or biochemistry; also affecting response to any particular intervention. With that in mind, authors also reported that (group) scores on one of their primary outcome measures - the SRS - were significant, indicative of some positive change noted to behaviour over the course of the intervention period. I say this bearing in mind that this was an open-trial, where everyone took sulforaphane and everyone knew that they were taking sulforaphane (including the parents who did the scoring). As for those potential 'best-responders' to sulforaphane use, we are told that: "Eight participants had a clinical response compared to seven who were classified as non-responders."

Then to those metabolomic results, and from a total of nearly 700 compounds identified in urine, approaching 80 of them seemed to show some correlation with the behavioural symptom changes noted. They were put into various categories depending on their biochemical form and/or action, and correlations with behavioural scores (and significance) were presented. Some of the best correlations that I could see were with regards to sphingomyelin metabolism. The authors did seem a bit surprised by results in this area, but added: "It is not clear how sulforaphane might alter sphingomyelin metabolism or availability and whether this is related to clinical benefits, but if this association is confirmed, it has important clinical and treatment implications." I daresay that examination of sphingomyelin metabolism in other contexts (see here for example) might be revealing, particularly in the context of other behavioural/psychiatric labels [3] that could (and do) overlap with autism.

There is a further scheme of work to be followed when it comes to sulforaphane and autism on the basis of these and other scientific results [4]. I'd also suggest that the continued incorporation of the science of metabolomics is a good thing, and adds a further tier of investigation when it comes to studying intervention more generally in the context of autism. It's also an important step in (eventually) coming up with a 'test' for who might be a best-responder to the use of sulforaphane and perhaps associated compounds...

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[1] Bent S. et al. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Molecular Autism. 2018; 9: 35.

[2] Singh K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-5.

[3] Castillo RI. et al. From Molecules to the Clinic: Linking Schizophrenia and Metabolic Syndrome through Sphingolipids Metabolism. Frontiers in Neuroscience. 2016;10:488.

[4] Sedlak TW. et al. Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study. Mol Neuropsychiatry. 2018 May;3(4):214-222.

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A poo(p) transplant for depression and anxiety?

Contrary to the title of this post - "A poo(p) transplant for depression and anxiety?" - I don't think we are yet in a position to say that Fecal Microbiota Transplantation (FMT) is ready to go 'mainstream' as an approved treatment for depression and/or anxiety. I do however, think that the findings reported by Shunya Kurokawa and colleagues [1] provide evidence for a further, more controlled, scheme of research on this topic.

Based on their following a small-ish group of patients diagnosed with "either Irritable Bowel Syndrome (IBS), Functional Diarrhea (FDr) or Functional Constipation (FC) who underwent FMT for the treatment of gastrointestinal symptoms and observation of psychiatric symptoms" authors report results before said poo(p) transplant and after 4 weeks based on ratings on various instruments pertinent to the presentation of depression and anxiety. Alongside "intestinal microbiota were measured" with a particular focus on the level of diversity of species that were present in pre- and post-FMT samples. I might also mention at this point, how something like IBS is not without it's own 'psychological' correlates as per other research (see here and see here).

Following an 'open-trial' methodology and including only a "small sample size with no control group", researchers reported some significant improvements in relation to those depression and anxiety symptom scores for some. Importantly too, they noted that potential FMT effects on mood seemed to be independent of effects on "gastrointestinal symptom change." Similarly: "There was a significant correlation between baseline Shannon index and HAM-D [Hamilton Rating Scale for Depression] score, and a correlation between Shannon index change and HAM-D improvement after FMT." This suggests that bacterial diversity might be something to look at as potentially explaining the psychological effects of FMT.

Reiterating that the Kurokawa findings are preliminary and hence, require quite a lot more further (independent) study, I find this topic to be an interesting one. Although there may be some 'consumer resistance' to the idea of FMT, for some people, this type of intervention is nothing short of life-saving (see here). The idea that a similar type of transplant *might* also hold some benefits for conditions/labels outside of something like Clostridium difficile (C. difficile) infection has already been noted in the peer-reviewed science literature (see here and see here for examples), including conditions characterised by behaviour and psychology. This alongside a growing interest in how mood and temperament might have some important connection to those trillions of wee beasties (the gut microbiome) that call us all home (see here). We'll see where this goes...

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[1] Kurokawa S. et al. The effect of fecal microbiota transplantation on psychiatric symptoms among patients with irritable bowel syndrome, functional diarrhea and functional constipation: An open-label observational study. J Affect Disord. 2018 Apr 12;235:506-512.

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Immunoadsorption and ME/CFS: observations from a small proof of concept study

Immunoadsorption refers to "an alternative blood purification technique... used to eliminate pathogenic antibodies." I'll freely admit that I don't know an awful lot about this procedure, so approach the findings reported by Carmen Scheibenbogen and colleagues [1] with a degree of naivety with regards to 'usefulness' and also important issues such as safety.

Authors report preliminary findings from their 'proof of concept' study, using immunoadsorption (IA) on a small group of adults (N=10) diagnosed with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) who also presented with "infection-triggered disease onset, disease severity according to the Bell scale of ≤ 50 of 100, and elevated levels of ß2 antibodies." The Bell scale by the way, seems to refer to a scale developed by David Bell with scores ranging from 0 to 100 to denote fatigue symptoms, post-exertional malaise (PEM) and 'ability to work full-time'. A lower score denotes more severe symptoms. The description "elevated levels of ß2 antibodies" refers to antibodies against ß2 adrenergic receptors; receptors which are found throughout the body and are involved in various biological tasks including smooth muscle relaxation and regulating certain cardiac functions. As the authors note: "Antibodies to ß2... receptors had been reported in various other diseases including dilatative cardiomyopathy, postural tachycardia, regional pain syndrome, Alzheimer, Sjögren’s syndrome, asthma and others." The 'antibodies' bit implies that the body is failing to recognise these receptors as 'self' and instead wrongly mounts an immune response against them.

Scheibenbogen et al mention that during their other studies on ME/CFS [2] they noted "a sustained decline of pretreatment elevated ß2 antibody levels in clinical responders to rituximab treatment." The rituximab bit refers to some initially encouraging results [3] from the use of this treatment that, unfortunately, do not seem to have weathered more rigorous scientific scrutiny (see here). Authors further hypothesised that IA might be a route to "removing autoantibodies" and specifically those "elevated antibodies against β2."

Results: "Prior to IA all patients had elevated antibodies against β2, in addition 7 patients against ß1 adrenergic receptors and 6 patients against both M3 and M4 acetylcholine receptors." Autoantibodies in many of the participants included for study went beyond just those against β2.

Following quite a few cycles of IA - "IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered" - authors reported that: "Levels of ß2 adrenergic antibodies were low to undetectable in 9 of 10 patients." This is kinda what would be expected following IA (bearing also in mind that: "After the 5th IA cycle all patients received 25 g IgG i.v." also known as IVIG).

Insofar as the clinical course of participants' presented symptoms, well, it was a bit of a mixed bag. So: "A rapid improvement of several symptoms was reported by 7 of these 9 patients during IA. However, none of the patients completely recovered and 5 patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms." I'm happy to report that the authors did utilise the wonderful technology headed under the term actigraphy (activity monitoring) as per their assessing participants step counts "by a Vivofit activity tracker." Such objective activity monitoring is sadly lacking from many other studies on ME/CFS (see here for example). Again however, the step counts reflect an initial 'good start' for IA followed by a not-so-good finish...

"Taken together, this pilot study provides evidence that IA can effectively remove ß2 and M3/M4 autoantibodies in CFS/ME and can result in rapid moderate to marked symptom improvement." I wouldn't disagree with the authors' conclusions but would perhaps suggest that the current results as they stand don't yet provide authoritative evidence for a beneficial effect of IM in the longer term. More [controlled] study is required.

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[1] Scheibenbogen C. et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672.

[2] Loebel M. et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016; 52: 32-39.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898.

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"A pilot study of high-dose intravenous immunoglobulin 5% for autism"

Intravenous immunoglobulin (IVIG), the treatment of choice for "patients with antibody deficiencies" [1] has some research history when it comes to autism (see here).

Quite a few years back, I remember some chatter about the use of IVIG for at least a subset of children/adults diagnosed with autism [2]. Interest in IVIG subsequently waxed and waned, partly as a result of some politics 'accompanying' research but also because of things like the cost of such an intervention.

Judging by the recent results published by Isaac Melamed and colleagues [3] however, it looks however, like IVIG *might* be coming back into research fashion...

So: "we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD [autism spectrum disorder]." The words "immune dysregulation" and "neuroinflammation" are mentioned a few times in the Melamed paper so you can probably work out the reason(s) why IVIG was examined. I might add that this study appears to have been registered with ClinicalTrials.gov too (see here).

This was a pilot study so, of course, one always needs to be a little bit cautious when it comes to the study and any findings. But, from what I can see, the authors put in place quite a few 'primary' and 'secondary' endpoints covering various aspects of behaviour - "Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]" - and also some 'experimental' biomarkers of immune function in this study. That's quite a comprehensive battery all-in-all.

Based on the use of a "high-dose intravenous immunoglobulin" (1g/kg dose of Gammaplex 5%) for ten 21-day treatment cycles with some 14 research participants diagnosed with autism, researchers reported some signs of 'effect'. Behaviourally speaking, they talk about significant improvements in core areas such as reciprocal social interaction, communication and repetitive and/or stereotyped behaviours being observed. This, alongside significant reductions in "numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation." In short, IVIG seemed to show effects and, importantly: "no subjects withdrew due to an adverse event" providing some well needed 'first, do no harm' data.

One study - an open label study at that - does not an evidence base make. Not even close, and that's despite other open label studies also being published [3] in this area. One also needs to bear in mind that IVIG is a blood product typically derived from more than one donor which, although screened for various infectious diseases, might still leave some people a little nervous about its use.

But... results such as the ones from Melamed cannot be easily ignored. Not least set within the context of a growing interest in immune function being *related* to some autism (see here for example) and specifically where 'regression' seems to be part and parcel of symptom onset (see here and see here), further [controlled] investigations are required. And that includes what happens to any behavioural / immunological gains / changes as and when IVIG intervention is stopped too...

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[1] Jolles S. et al. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. 2005;142(1):1-11.

[2] Gupta S. Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999 Mar;14(3):203-5.

[3] Melamed IR. et al. A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. Autism Res. 2018 Feb 10.

[4] Boris M. et al. Improvement in children with autism treated with intravenous gamma globulin. Journal of Nutritional & Environmental Medicine. 2005; 15.

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"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

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[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

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"Mitochondrial Modifying Nutrients" and chronic fatigue syndrome: a pilot study

"Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS)" was the starting point for the study results reported by Ranjit Menon and colleagues [1].

Detailing findings -  "open-label trial" findings - following use of a 'nutraceutical combination' in a small number of participants with CFS, researchers produced evidence that further investigations might be needed. The trial protocol for their investigation can be viewed here. The 'combination' under inspection included "primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins"; many of which have been shown to act on various "mitochondrial targets" in the context that mitochondria might play a role in at least some cases of CFS (see here for example), but not necessarily all (see here). Indeed, I'll draw your attention when other groups have talked about nutraceutical 'intervention' (see here) in the context of mitochondria and CFS previously (see here and see here).

Over the 16 weeks of the trial period, researchers quite regularly assessed various parameters relating to the core feature of fatigue (based on use of the Chalder Fatigue Scale) and various mood, sleep and general health variables. They observed that alongside "a significant improvement in fatigue symptoms across [the] treatment period on the Chalder Fatigue Scale" there were also some potentially important differences noted in other measures too. Not least with "clinician-reported symptom-improvement" in mind.

Obviously the emphasis on the Menon results being an open trial (i.e. not blinded/masked, not randomised, with no control group), and very much, a small open trial, mean that these are preliminary findings and shouldn't yet be informing any research or clinical opinions. The additional fact that no objective 'actigraphic' measure of physical functioning was included for study is something else to bear in mind. Such results *should* support further research; indeed, one would hope that in this new era of interest and 'changing perspectives' with CFS in mind (see here), many more investigations in this thread would be forthcoming.

And whilst on the topic of clinical trials for CFS, the news out of Norway when it comes to the use of Rituximab is not looking too good despite a previously promising start [2]. No-one said it was going to be easy...

To close, I've nabbed a screenshot of a picture from the film Unrest that I think is starting to take on an almost iconic status...

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[1] Menon R. et al. Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study. Advances in Integrative Medicine. 2017. Nov 15.

[2] Fluge Ø. et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358.

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Metformin to tackle medication induced weight gain in autism continued

The results of the open-label extension trial on the use of "Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism" reported by Benjamin Handen and colleagues [1] is blogging fodder for today. Continuing a research interest from this group (see here), the idea that weight and related side-effects from certain antipsychotic medicines can be managed by a drug readily used to treat type 2 diabetes receives yet more support.

Last time around [2] researchers showed that under double-blind, placebo controlled conditions, metformin was fairly well-tolerated and did aid in "decreasing weight gain associated with atypical antipsychotic use" in children and young adults diagnosed with an autism spectrum disorder (ASD). This latest publication detailed what happened when everyone - well, 85% of the original cohort - went on metformin in terms of their body mass index (BMI) and "additional body composition and metabolic parameters" for an additional 16 weeks.

Results: well, as would probably be expected, "participants initially taking placebo during the RCT [randomised controlled trial] had reduced BMI z-scores" when metformin was introduced. For those who were already taking metformin during the original trial, prior reductions in BMI were maintained but they "did not experience additional weight loss." I might also add that 'fairly well-tolerated' meant that: "Three participants discontinued treatment due to an adverse event."

These are important findings and add to other preliminary research findings in this area [3]. I know many people (including myself) have some reservations about adding in medicines to treat the side-effects of other medicines (as well as the conditions for prescribing antipsychotics in the first place [4]), but given what elevated BMI scores can mean to physical health and associated health risks, this is one occasion where intervention might be truly life-saving (with appropriate clinical monitoring assumed). Further studies are indicated.

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[1] Handen BL. et al. A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension. Journal of the American Academy of Child & Adolescent Psychiatry. 2017. Aug 19.

[2] Anagnostou E. et al. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.  JAMA Psychiatry. 2016 Sep 1;73(9):928-37.

[3] Wink LK. et al. Brief Report: Metformin for Antipsychotic-Induced Weight Gain in Youth with Autism Spectrum Disorder. J Autism Dev Disord. 2017 Jul;47(7):2290-2294.

[4] Jackel C. et al. Factors Associated with Developmental Behavioral Pediatricians Prescribing Psychotropic Medication to Children with Autism Spectrum Disorder: A Study of Three DBPNet Sites. J Dev Behav Pediatr. 2017 Aug 10.

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