Saturday, 27 May 2017

Low dose suramin and autism: a small RCT with potentially big results

'Low dose' has been a feature of my autism research reading this week; first starting with the results from Dan Quintana and colleagues [1] talking about some important effects following intranasal delivery of low dose oxytocin and then moving on to the primary reason for this entry with results from Robert Naviaux and colleagues [2] (open-access) continuing a research theme looking at suramin and autism (see here for some background).

For those interested in the oxytocin-autism research base, I can recommend following Dr Quintana on Twitter (find him here).

In relation to the Naviaux findings  - the "Suramin Autism Treatment-1 (SAT-1) trial" - well, they are open-access but I want to provide some overview and then a little bit of discussion. I might add that this research team are making research waves in several areas of medical science as per their research foray into chronic fatigue syndrome (CFS) recently (see here). Such 'metabolomic' research is pertinent to their autism research too.

This time around as on previous research occasions, the focus was on suramin - the "century-old sleeping sickness drug" - and, as far as I can see, the first time said drug has been tested experimentally with children diagnosed with an autism spectrum disorder (ASD). The accompanying ClinicalTrials.gov trial entry is here.

As per the title to this blog entry, this was a small trial including only 10 participants, all male, aged between 5-14 years old. This was a randomised-controlled trial (RCT) with a placebo element to it too, so half of the participants got suramin - "a single, intravenous infusion of suramin (20 mg/kg)" - and half got saline as a control. Alongside looking at behaviour and functioning, researchers also took blood and urine samples "for safety and toxicity monitoring at 5 times throughout the study." This was accompanied by quite a bit of effort to look at the possibility of adverse events related to suramin or placebo administration.

Results: "A single intravenous dose of suramin was associated with improved scores for language, social interaction, and decreased restricted or repetitive behaviors measured by ADOS, ABC, ATEC, and CGI scores. None of these improvements occurred in the five children who received placebo." The authors also do the right thing by stating: "The generalizability of these findings is unknown." I'm particularly impressed that the ATEC gets a showing given the rise and rise of this autism research tool (see here) in various placebo-controlled contexts (see here).

In relation to the safety aspect to suramin, well, it seemed to do alright. We are told that: "Extensive monitoring revealed no serious toxicities" so one can assume that the 'first, do no harm' tenet was upheld in this trial. But there was one important side-effect noted: "Five children who received suramin developed a self-limited, evanescent, asymptomatic, fine macular, patchy, morbilliform rash over 1–20% of their body." The rash was short-lived and did not require specific attention/intervention but it's worthwhile noting it especially when nothing similar was reported in the placebo group.

Going back to the mention of this research group delving into CFS with metabolomics in mind, so similar results are reported on the basis of examination of plasma samples from participants. Various biological pathways seemed to be affected by the infusion of suramin, not least "the importance of the cell danger response (CDR) [3]... and purinergic signaling." Interestingly, authors also noted effects in relation to "1-carbon, folate, methionine, and cysteine metabolism" too, potentially linked to other findings independently reported in relation to autism (see here for example).

Reiterating again that this was a small study (albeit using the gold-standard in scientific methodologies) these results are rather interesting and potentially quite important. They most definitely point to the requirement for further large-scale studies to look at any effects in a larger participant group and to 'zoom in' on potential best-responders to this type of intervention. I end with an important conclusion from the authors who again, have not over-stated their findings:

"Suramin is not approved for the treatment of autism. Like many intravenous drugs, when administered improperly by untrained personnel, at the wrong dose and schedule, without careful measurement of drug levels and monitoring for toxicity, suramin can cause harm. Careful clinical trials will be needed over several years at several sites to learn how to use low-dose suramin safely in autism, and to identify drug–drug interactions and rare side effects that cannot currently be predicted. We strongly caution against the unauthorized use of suramin."

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[1] Quintana DS. et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry. 2017 May 23;7(5):e1136.

[2] Naviaux RK. et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Annals of Clinical & Translational Neurology. 2017. 26 May.

[3] Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014; 16: 7-17.

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ResearchBlogging.org Naviaux, R., Curtis, B., Li, K., Naviaux, J., Bright, A., Reiner, G., Westerfield, M., Goh, S., Alaynick, W., Wang, L., Capparelli, E., Adams, C., Sun, J., Jain, S., He, F., Arellano, D., Mash, L., Chukoskie, L., Lincoln, A., & Townsend, J. (2017). Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.424

Friday, 26 May 2017

On ADHD medication and motor vehicle crashes

"Among patients with ADHD [attention-deficit hyperactivity disorder], rates of MVCs [motor vehicle crashes] were lower during periods when they received ADHD medication."

That was the research bottom-line discussed by Zheng Chang and colleagues [1] who continue a theme on how managing/treating the symptoms of ADHD can often have some profound effects on those diagnosed with ADHD and also the wider population.

The outcome measure on this occasion was MVCs; in particular: "Emergency department visits for MVCs" as assessed from data from the "Truven Health Analytics MarketScan Commercial Claims and Encounters databases." I've talked about the application of this resource in a research context before on this blog (see here). Such Emergency Room (ER) (also known as Accident & Emergency (A&E) here in Blighty) visits were assessed for those with and without a diagnosis of ADHD or those in receipt of  "ADHD medication between January 1, 2005, and December 31, 2014." Authors compared the "risk of at least one MVC between patients with ADHD and matched controls."

The results, based on quite a large number of people (2 million+) diagnosed with ADHD, suggested that: "Patients with ADHD had a significantly higher risk of an MVC than their matched controls." Medication for ADHD - of which over 80% of the cohort with ADHD were taking - seemed to affect the risk of MVCs as per the sentence introducing this post. Indeed authors noted: "months with ADHD medication were associated with a 12%... lower risk of MVCs in male patients with ADHD relative to unmedicated months and a 14%... lower risk of MVCs in female patients with ADHD." The figures actually got even better for risk reduction of MVCs when analysed at the "within-individual" level: "men with ADHD were 38% less likely to have MVC events during medicated months relative to unmedicated months" and for women, this figure went up to 42% less likely to have an MVC during medicated months. All-in-all, treating ADHD with medication meant less visits to the ER for motor vehicle crashes.

Accepting that the use of medication for ADHD (or anything else) is not something that should ever be entered into lightly, there is quite a large body of evidence emerging suggesting that specific preparations at least, are both safe and reliable in terms of tackling the symptoms of ADHD (see here). Indeed, clinicians are seemingly becoming a lot more comfortable with employing pharmacotherapeutic strategies for ADHD (see here) probably in part, due to the effectiveness of available medications and their pretty good safety profile. I say all that noting that medication is not necessarily the only tool in the arsenal (see here and see here for examples).

Of course there are caveats to this latest set of results; not least that this was a study looking at two variables (MVCs leading to ER attendance and ADHD medication(s)) and so might potentially have missed other data/factors (e.g. MVCs not requiring ER attendance). One also assumes that ADHD medication prescriptions were also being taken uniformly every day as indicated...

Still, there is good reason to think that ADHD medication might be 'doing what it says on the tin' in terms of tackling issues such as inattention and impulsivity and how this had knock-on effects for MVCs requiring hospitalisation. Indeed, thinking also about the safety of other motorists who might have potentially benefited from the behaviour of those drivers with ADHD under medication, one can only see the life-changing potential of these informative results...

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[1] Chang Z. et al. Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes. JAMA Psychiatry. 2017. May 10.

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ResearchBlogging.org Chang Z, Quinn PD, Hur K, Gibbons RD, Sjolander A, Larsson H, & D'Onofrio BM (2017). Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes. JAMA psychiatry PMID: 28492937

Thursday, 25 May 2017

Blood heavy metal levels and autism (yet again)

"Data showed that the children with ASD [autism spectrum disorder] had significantly (p < 0.001) higher levels of mercury and arsenic and a lower level of cadmium."

And... "It is desirable to continue future research into the relationship between ASD and heavy metal exposure."

Those sentences come from the study by Huamei Li and colleagues [1] continuing a research theme regarding (generally) elevated levels of heavy metals being detected in those on the autism spectrum (see here). Yes, I know that this kind of research is not always met with great appreciation (see here) but the suggestion that the heavy metal burden seems to be quite a bit higher in the autistic population is not something that can just be ignored. More so when it might actually be treatable (with no medical or clinical advice given or intended)...

There are numerous other examples in the peer-reviewed science literature that I could give where the heavy metal burden has been found to be elevated in relation to autism. Indeed, if someone is looking for yet another systematic review and meta-analysis topic, there you go - you're welcome. Personally, I think we've reached the point where the questioning needs to move on to (a) the possible sources of those heavy metals and (b) whether 'exposure amount' is the sole reason for the elevations in relation to autism over and above issues with the biology around 'detoxifying' said metals. Answers are not likely to be simple but questioning has to continue...

To close, he was always my favourite James Bond...

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[1] Li H. et al. Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biol Trace Elem Res. 2017 May 8.

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ResearchBlogging.org Li H, Li H, Li Y, Liu Y, & Zhao Z (2017). Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biological trace element research PMID: 28480499

Wednesday, 24 May 2017

Irritable bowel syndrome (IBS) as a risk factor for bipolar disorder

"Only irritable bowel syndrome (IBS) emerged as a risk factor for BD [bipolar disorder] supported by convincing evidence."

So said the results of the umbrella review of systematic reviews and meta-analyses by Beatrice Bortolato and colleagues [1] looking at the various environmental risk factors potentially linked to the diagnosis of bipolar disorder. I might add that this is a topic that has been discussed before on this blog (see here and see here for examples).

If the systematic review / meta-analysis represents the top of the research methodology hierarchy, a review including a number of systematic reviews and meta-analyses represents the cherry on top. Indeed, there is a growing trend of this kind of research (see here).

The authorship names included on the Bortolato paper are not unfamiliar to this type of study methodology (see here) and specifically, the focus on psychiatric and somatic variables often being intertwined. This time around attentions turned to bipolar disorder, previously called manic depression, and a survey of 16 research publications identified listing over 50 "unique environmental risk factors for BD." The report of a possible link (with 'convincing evidence') between IBS and BD consolidates the idea of a gut-brain axis. Authors also detailed a few other factors as showing weaker but not necessarily less important connections to BD including childhood adversity, obesity and asthma. Focusing in on asthma in particular - a condition again previously talked about in the context of BD - I am wondering whether there are quite a few more generalisations connected to this diagnosis within the context of psychiatric labels (see here and see here)?

Of course, more science is indicated on the hows-and-whys of connections such as the one between IBS and BD and the tantalising prospect of new intervention avenues if such a relationship is further confirmed. Minus any medical or clinical advice, I'm specifically thinking about how alterations to the gut microbiome accompanying cases of IBS might mean that talk of things like probiotics affecting the symptoms of IBS (see here) could be applicable to the presentation of [some] BD too. That and the idea that certain dietary elements might also be important to cases (see here and see here)...

To close, I know that the past few days have not exactly been ones for smiling, but if some smiles and laughter are what you need, then the animal kingdom can provide them...

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[1] Bortolato B. et al. Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses. Bipolar Disord. 2017; 00: 1–13.

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ResearchBlogging.org Bortolato, B., Köhler, C., Evangelou, E., León-Caballero, J., Solmi, M., Stubbs, B., Belbasis, L., Pacchiarotti, I., Kessing, L., Berk, M., Vieta, E., & Carvalho, A. (2017). Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses Bipolar Disorders DOI: 10.1111/bdi.12490

Tuesday, 23 May 2017

"there is no single way for a brain to be normal" (or how 'neurotypical' is a nonsense)

I'm not usually so forthright with my posts on this blog, but today I'm being a little more bullish as I talk about an editorial from Simon Baron-Cohen [1] titled: "Neurodiversity – a revolutionary concept for autism and psychiatry."

The crux of the SBC paper is the suggestion that use of the term 'disorder' specifically with autism in mind might have certain connotations - "Disorder should be used when there is nothing positive about the condition" - and until the "biomedical mechanistic cause of a disorder becomes known" some thought should go into the way autism for example, is described.

The author seems to come down on something between 'difference' and 'disability' as being valid replacements, bearing in mind the wide - very wide - heterogeneity that is the autism spectrum and the fact that 'disorder' is still very prominent in the formal clinical descriptions of autism and related diagnoses (see here). Indeed on the topic of 'biomedical mechanistic causes' and [some] autism, well, there is already some evidence for this (see here)...

Personally, I don't want to get involved in such disorder/difference debates. I say this on the basis that (a) people have their own ideas, descriptions and motivations for talking about what autism is and isn't to them (and who I am to question them and their views) and (b) from a research and clinical point of view, such linguistic differences make little difference when it comes to whether someone does or does not reach critical cut-off points for being on the autism spectrum and the subsequent help and support required. These are cultural issues not fundamental research or clinical ones (although I daresay some people would argue against that last point).

What I do however want to mention about the Baron-Cohen article is that specific sentence described in the title of this post - "there is no single way for a brain to be normal" - in relation to neurodiversity [2] and how said phrase helps dismantle a problematic term present in various autism circles: neurotypical (NT).

I see the word neurotypical (NT) banded about a lot these days including in the peer-reviewed domain. I assume from the name that the term describes 'others' who within the vast spectrum of diversity - neuro and otherwise - are, in relation to autism, not positioned on the autism spectrum. It's basically an 'us-and-them' term, which means not-autism (or other condition where similarly applied).

The problem I have with this term relates to the questions: what exactly is neurotypical? and who actually falls under such a description?

OK, we have the first bit - neuro - which is also used/misused a lot these days (together with some scepticism) I assume referring to the brain. Autism is often described in terms of the brain (structure, connectivity, 'wiring') as mentioned in the Baron-Cohen text, with some groups even talking about the possibility of an 'autistic brain' (see here). More precisely 'neuro' probably better describes the nervous system so one might instead look to the term 'autistic nervous system' as being more accurate (bearing in mind the brain is but one thinking organ in the body!). The second part - 'typical' - on it's own means just that: classic, quintessential, representative. Put them both together and the suggestion is that there is an 'average, representative brain / nervous system' in the population that is distinct from the 'autistic brain / nervous system'.

Why is this problematic? Well, this is where the concept of 'identity' has I think perhaps overstretched itself.

The 'autistic brain'? Bullshit (pardon my language). As I've said before on this blog, there is nothing in the peer-reviewed science literature to yet say that the brains / nervous system of everyone diagnosed as being on the autism spectrum are in any way universally different from those not reaching thresholds for the autism spectrum (see here). Nothing. Not one article. Indeed, with the greater recognition that autism is probably a plural condition covered by a singular label (see here), the likelihood that something / anything will universally define the 'autistic brain' is becoming even more distant. Y'know, much like the fading concept of an autistic gene that's taken so long to consign to the research dustbin/trashcan. I say all this even before we start to add-in the idea that autism rarely exists in some sort of diagnostic vacuum (see here) in these days of ESSENCE (see here).

OK, you might say that 'typical' could be stretched to include a wider spectrum of brains / functioning / thinking rather than just one singular thing? Well, that's true but here's another issue: at what point does 'typical' then turn into 'atypical'? The inference is that alongside the neurotypical there is something akin to the neuroatypical. Where are these boundaries of neurotypical and neuroatypical? Do the boundaries shudder to an abrupt halt the moment cut-off points for a diagnosis of autism are reached or surpassed? Does this also mean that other labels such as attention-deficit hyperactivity disorder (ADHD) are also outside of the term neurotypical? Really? On what evidence?

Then also there are the various observations that the presentation(s) of autism - the symptoms / characteristics / label - might actually be quite fluid across different people according to variables such as age or environment and how that further complicates the neurotypical concept. I've talked for example, before about how something like diagnostic stability is perhaps not as stable as many people might think when it comes to some autism (see here) and indeed, in relation to other over-represented comorbidity too (see here). Does this mean that those for example, currently not fulfilling the diagnostic criteria for autism but having previously done so at some previous point have somehow 'transitioned' from autism to neurotypical? Again, really? On what evidence?

I could go on (and on) about the other problems with the concept of neurotypical (e.g. the problem of objectively measuring thinking styles, etc) but I won't. All I'll say is that in the age of 'show me the evidence' please do show me the evidence - any evidence - that neurotypical is anything other than an alternative phrase to 'not-autism' or at least not meeting the current cut-off thresholds for a diagnosis of autism or related label.

And, on the basis of the points I've raised in today's post, how then can science continue to justify it's use when the description of neurotypical is, by all accounts, a nonsense?

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[1] Baron-Cohen S. Editorial Perspective: Neurodiversity - a revolutionary concept for autism and psychiatry. J Child Psychol Psychiatry. 2017 Jun;58(6):744-747.

[2] Armstrong T. The myth of the normal brain: embracing neurodiversity. AMA J Ethics. 2015 Apr 1;17(4):348-52.

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ResearchBlogging.org Baron-Cohen S (2017). Editorial Perspective: Neurodiversity - a revolutionary concept for autism and psychiatry. Journal of child psychology and psychiatry, and allied disciplines, 58 (6), 744-747 PMID: 28524462

Monday, 22 May 2017

"a gluten-related subgroup of schizophrenia"?

A quote to begin this post: "this preliminary study demonstrates that altered AGDA [antibodies against gliadin-derived antigen] levels in the circulation are associated with schizophrenia and could serve as biomarkers for the identification of a schizophrenia subgroup that may need an alternative therapy or precision treatment."

So said the findings reported by McLean and colleagues [1] (open-access) looking at an area of some interest to this blog (see here) on how dietary gluten might show something of an important relationship to at least some cases of schizophrenia. Just in case you weren't aware, there is quite a history when it comes to gluten and schizophrenia (see here) as per the very forward-thinking of people such as Curt Dohan and Karl Reichelt.

Researchers on this latest occasion set about looking in a little more detail at the suggestion that circulating anti-gliadin antibodies (AGAs) reflective of an immune response to a component of dietary gluten might show some connection to schizophrenia. Indeed they note that "all the tests for circulating AGAs in schizophrenia have been developed with mixtures of full-length native gliadins consisting of ~300 amino acid residues" suggesting that such a scatter gun approach may have included epitopes "that are unlikely to survive digestion in the gut." So, they instead "measured plasma levels of IgG and IgA against indigestible peptide fragments derived from γ- and α-gliadins" in archived plasma samples from "169 patients with schizophrenia and 236 control subjects."

The results - based on the use of an "In-house ELISA for antibodies against gliadin-derived antigens" - were rather intriguing. So: "There was no significant difference in the levels of plasma antibodies against native gliadins between the patient group and the control group." If I'm reading this right, this finding is in contrast to other independent research occasions [2]. Indeed, when it came to looking at both IgA and IgG plasma anti-gliadin antibodies, there was no significant difference between the schizophrenia and non-schizophrenia participants as groups.

But... when it came to a specific gliadin (γ-Gliadin) derived fragment  - AAQ6C - with the amino acid sequence HPKCSIMRAPFASIVAGIGGQYRD - researchers reported on something potentially important to see: "patients with schizophrenia had significantly higher levels of plasma anti-AAQ6C IgG than control subjects." Importantly too, authors also noted that anti-psychotic medication did not appear to influence their antibody results. This was important given that seemingly all of the participants diagnosed with schizophrenia were taking one or more of this class of medicine. In line with the opening quote to this post, the authors make a preliminary foray into the possible 'biomarker' usefulness of the various anti-gluten antibodies for schizophrenia. I have to say on this point however, that the data is not that impressive as things currently stand.

There is more to do when it comes to the possible effects of dietary elements containing gluten (and casein) in relation to cases of schizophrenia. This work adds something to the idea that diet can affect psychiatry/behaviour/development but what is perhaps missing is the recognition that schizophrenia is probably a heterogeneous and plural condition (see here and see here for examples) and as such, not every case is going to be gluten and/or casein-related. I do agree with the authors that more research is needed in this area alongside the idea that intervention via either dietary changes [3] and/or other options might also be on the research agenda...

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[1] McLean RT. et al. Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational Psychiatr. 2017. May 9.

[2] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[3] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophrenia Res. 2012;140(0):262-263.

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ResearchBlogging.org McLean RT, Wilson P, St Clair D, Mustard CJ, & Wei J (2017). Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational psychiatry, 7 (5) PMID: 28485731

Saturday, 20 May 2017

Gastrin-releasing peptide and autism continued

Yet another 'continued' or 'part 2' short post for you today, building on some previous - very preliminary research - talking about the use of gastrin-releasing peptide (GRP) and autism (see here).

The authors included on the paper by Josemar Marchezan and colleagues [1] are familiar ones to this part of the autism research landscape as per the other occasions that members of this group have looked at / talked about GRP and autism in the peer-reviewed domain.

GRP is all about a compound that 'does what it says on the tin' insofar as stimulating the release of gastrin from specialist cells in the stomach. This in turn leads to the secretion of gastric acid among other things and onward aids the digestion of food.

This time around Marchezan et al describe the results of a controlled trial on the use of GRP (vs. placebo) in a small group of boys (N=10) diagnosed with autism. This is a step-up from their previous research efforts in this area talking about a case series report and an open (non-blinded, non-placeboed?) study. Participants were given the same amount of GRP (160 pmol/kg) over the same number of days (4 consecutive days) as that detailed in their previous studies. This time around, the Aberrant Behavior Checklist (ABC) scale was the outcome measure of choice.

Results: well, let's put it one way, they weren't exactly astounding in terms of any positive effects from the use of GRP over such a short space of time. This was exemplified by the authors use of "no statistical difference" when it came to looking at quite a lot of the data obtained during the investigation comparing GRP to placebo. On the plus side there were "no adverse effects, changes in vital signs, or laboratory abnormalities associated with the use of GRP" so the whole 'first do no harm' bit seems to be intact, at least in the short-term.

Whilst it would be easy to sweep such results under the 'did not work' carpet, I am however minded to go with the authors' suggestion that "further research with other designs and a larger sample size to evaluate the efficacy and safety of GRP in children with autism" would be a step forward. I say this on the basis that hypochlorhydria - low levels of gastric acid - is not something completely unknown to parts of the autism spectrum (see here) and does suggest some *possible* involvement for something like GRP in specific cases of autism.

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[1] Marchezan J. et al. A Placebo-Controlled Crossover Trial of Gastrin-Releasing Peptide in Childhood Autism. Clin Neuropharmacol. 2017 Apr 27.

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ResearchBlogging.org Marchezan, J., Becker, M., Schwartsmann, G., Ohlweiler, L., Roesler, R., Renck, L., Gonçalves, M., Ranzan, J., & Riesgo, R. (2017). A Placebo-Controlled Crossover Trial of Gastrin-Releasing Peptide in Childhood Autism Clinical Neuropharmacology DOI: 10.1097/WNF.0000000000000213