Baclofen is back: "Baclofen as an adjuvant therapy for autism"

"Our data support [the] safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD [autism spectrum disorder]."

So said the findings reported by Seyedeh-Mahsa Mahdavinasab and colleagues [1] talking about the use of baclofen as an add-on medicine in the context of risperidone use in relation to autism. Baclofen by the way, is typically known as "a gamma-aminobutyric acid (GABA) agonist" (binds to the GABA receptors and activates them) which accounts for its use as "a skeletal muscle relaxant" given the inhibitory function of GABA and GABA receptors.

Why the 'baclofen is back' sentiment expressed in the title of this post? Well, a few years back there was some excitement about a compound called STX209 otherwise known as arbaclofen in the context of a genetic condition manifesting autistic signs and symptoms (see here) and autism itself. Arbaclofen is an enantiomer (mirror image in a chemical sense) of baclofen, but unfortunately fell by the wayside after some less than impressive results emerged from clinical trials (see here). Arbaclofen might have been kicked into the long grass for now but baclofen it seems, is still on the autism research agenda...

Researchers report results based on a "10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD." Risperidone is an antipsychotic which is indicated for selective use with children with autism (see here) specifically to treat/manage aggressive and challenging behaviours. They reported that several outcome measures saw a change - a positive change - specifically in relation to hyperactivity behaviours which can often accompany aggression. Importantly, they also noted that during and after 10 weeks of add-on baclofen use, adverse events were reported to be at a minimum.

There is more to do in this area before any sweeping generalisations are made. I personally would like to see more data on potential best- and non-responders in the context that GABA is still a topic of interest to autism research (see here). I know also that some people might be a little put-out by the idea that more medication is added to the lives of young children with autism and worries about how this might impact them in later years. We need a lot more data.

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[1] Mahdavinasab SM. et al. Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry. 2019 Apr 12.

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Add-on nutraceuticals for depression?

It came as no surprise to me that the systematic review and meta-analysis article by Jerome Sarris and colleagues [1] found what it did in relation to the use of [certain] adjunctive (add-on) nutraceuticals alongside antidepressants to reduce depressive symptoms: some of them might actually be clinically useful.

With no medical or clinical advice given or intended, the authors report that "adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants" might be something to consider "for improving inadequate response to antidepressants." Dr Sarris was one among many authors who contributed to the 'personal view' paper titled: 'Nutritional medicine as mainstream in psychiatry' [2] which was also covered a while back on this blog (see here). This latest addition to that and other opinions [3] which covered the peer-reviewed literature on a variety of nutrients also found something of a mixed bag of results for various other compounds including the aromatic amino acid tryptophan, zinc, folic acid and vitamin C.

Quite a bit more science needs to be done in this area, not least around the hows and whys that the various preparations might exert some effect. Vitamin D has of course been covered quite a bit on this blog in relation to something like depression (see here for example) so that particular nutraceutical might already have a research head start compared to others. I'm also minded to suggest that the involvement of something like SAMe (S-adenosylmethionine) as an add-on treatment might also imply a role for epigenetic variables in relation to at least some depression [4]. And then there is the question of who might be best responders to such nutraceutical use which implies heterogeneity and possible plural depressions...

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[1] Sarris J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016. April 26.

[2] Sarris J. et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015 Mar;2(3):271-4.

[3] Sarris J. et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015 Oct;14(3):370-1.

[4] McGowan PO. & Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.

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Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, & Ng CH (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. The American journal of psychiatry PMID: 27113121

Yokukansan and treatment-resistant schizophrenia?

I'll freely admit that I'm no expert on yokukansan (YKS), the "traditional Asian herbal medicine" that comprises Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix. 

Yokukansan, in some circles also known as TJ-54, has however cropped up on my autism research radar before as per the very preliminary findings reported by Miyaoka and colleagues [1] (open-access) a few years back suggesting that the herbal combination might "be effective and well tolerated for treatment of severe irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech in patients with PDD-NOS or Asperger’s disorder." Those are the authors' words by the way, not mine.

Today I'm bringing another paper from Tsuyoshi Miyaoka and colleagues [2] (open-access available here) to the blogging table based on a a slightly improved methodological design and covering a different label in the DSM psychiatry 'bible': schizophrenia, and in particular, schizophrenia with a "history of documented treatment-resistant status." This study follows a stream of other peer-reviewed reports from Miyaoka et al on the topic of yokukansan and psychiatry (see here).

The latest paper is open-access but here are a few basics:

• Adult in-patients fulfilling DSM-IV-TR criteria for schizophrenia (N=120) and treatment-resistant status defined as "little or no response to treatment from at least two adequately dosed antipsychotic trials for at least 4 weeks including at least one second-generation antipsychotic (>600 mg/day of chlorpromazine equivalent)" among other things were included for study.
• Based on a "4-week, double-blind, placebo-controlled, fixed-flexible dose trial" participants were either allocated to receive TJ-54 or placebo (although I can't actually find the details of what the placebo consisted of). Baseline and follow-up measures including "psychopathology... assessed using the Positive and Negative Syndrome Scale (PANSS)" were conducted.
• "Existing medications at baseline remained unchanged, whereas initiation of other psychotropic medications was not permitted during the trial." This important point not only means that TJ-54 supplementation was an adjuvant (add-on) treatment for some but also offers some degree of 'stability' insofar as results not being attributable to other interventions being introduced over the study period.
• Results: the authors have tried to cover quite a few bases with their interpretation of the study findings both looking at results from an intention-to-treat (ITT) perspective and a per-protocol set. This means that different numbers of trial completers (or non-completers) are included in their analyses. The headline result: "TJ-54 showed a tendency of being superior to placebo in reduction total, positive, and general PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant." So after 4-weeks in general, there were potential changes following the use of TJ-54 but one can't rule out these being just due to chance.
• The devil however, might be in the detail when it comes to results. So: "compared to the placebo group, TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores for lack of spontaneity and flow of conversation, tension, and poor impulse control." Further: "When TJ-54 was combined with antipsychotics, the therapeutic benefits were significantly enhanced" highlighting how once again (see here) adjuvant therapy alongside antipsychotics might be the way forward for the management of some schizophrenia and beyond.
• Just as important for the discussions about possible effectiveness of TJ-54 are the author comments about side-effects: "Overall, TJ-54 was well tolerated with no severe or serious adverse effects." First, do no harm and all that.

The authors not only call for further research on TJ-54 and schizophrenia but are actually doing it themselves as per the comment: "The 4-week treatment duration was too short, which might have prevented us from exploring the efficacy of TKS [or should this be YKS?]. Therefore, now, we are conducting 12-week trial." Talk about getting on and doing it yourself eh?

I'm rather interested in these and other results [3] and their potential indications for at least some schizophrenia under certain circumstances. Treatment-resistant schizophrenia is a significant issue for a proportion of those diagnosed and can quite severely impact on quality of life for those in such a position [4]. Finding novel ways and means to overcome the various issues that a diagnosis of schizophrenia can potentially bring in that scenario is an important goal for psychiatry.

In terms of the possible explanations for the effects of TJ-54, well, once again we're left in head-scratching and speculation mode based on the current and other observations. Chuan-Hsun Yu and colleagues [5] (open-access) talk about some of the potential pharmacological implications of YKS supplementation focused quite a bit on the "antipsychotic implications of yokukansan." I'd be minded to suggest that alongside just monitoring potential effectiveness of YKS, science should really be doing quite a bit more on the biological processes potentially affected by supplementation, reiterating that YKS is a mixture and might have one than one biological effect.

To close: How to Swear Like a Brit. Not such a load of b******s.

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[1] Miyaoka T. et al. Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: a 12-week prospective, open-label study. BMC Psychiatry. 2012 Nov 29;12:215.

[2] Miyaoka T. et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, multicenter, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med. 2015;2015:201592.

[3] Miyaoka T. et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled trial (a Positive and Negative Syndrome Scale, five-factor analysis). Psychopharmacology (Berl). 2015 Jan;232(1):155-64.

[4] Englisch S. & Zink M. Treatment-resistant Schizophrenia: Evidence-based Strategies. Mens Sana Monogr. 2012 Jan;10(1):20-32.

[5] Yu CH. et al. Yokukansan and its ingredients as possible treatment options for schizophrenia. Neuropsychiatr Dis Treat. 2014 Sep 1;10:1629-34.

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Miyaoka T, Furuya M, Horiguchi J, Wake R, Hashioka S, Thoyama M, Murotani K, Mori N, Minabe Y, Iyo M, Ueno S, Ezoe S, Hoshino S, & Seno H (2015). Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, multicenter, double-blind, placebo-controlled trial. Evidence-based complementary and alternative medicine : eCAM, 2015 PMID: 25954314

Ginkgo biloba for ADHD?

I approach the paper by Fereshteh Shakibaei and colleagues [1] with some degree of caution save any suggestions that I am somehow 'promoting' the herb Ginkgo biloba for attention-deficit hyperactivity disorder (ADHD) or anything else. I'm not, but I am interested in the results of their placebo-controlled trial suggesting that "The G. biloba is an effective complementary treatment for ADHD" and their subsequent calls for further research into this potentially promising intervention.

As per the Medline Plus entry for Ginko biloba, irrespective of your views on herbal remedies and health (have you never heard of pharmacognosy?), there is a growing evidence base suggesting that such a preparation might have a place in the management of quite a few conditions/diagnoses. The caveat being that (a) quite a bit more research is needed, and (b) much like more mainstream pharmaceutics, such herbs are not without their contraindications when it comes to their use alongside other medicines. Treat your herbs et al like you would your typical medicines is the best advice, bearing in mind I don't give medical or clinical advice on this blog.

Shakibaei et al reported results looking at a group of children/adolescents over 6 weeks already in receipt of pharmacotherapy for their ADHD symptoms - "methylphenidate (20-30 mg/day" - to which either G. biloba was added - "80-120 mg/day" - or a placebo. They report that based on responses to the "Parent and teacher forms of the ADHD Rating Scale-IV (ADHD-RS-IV)" (something I've come across in my own research) compared with the placebo group "more reduction was observed with G. biloba" illustrative of potential positive changes to symptoms. The specific area of 'inattention' seemed to be positively affected by the use of G. biloba. The commonplace 'further studies are required' sentence completes the Shakibaei results.

This is not the first times that G. biloba has been discussed in the peer-reviewed domain with ADHD in mind (see here). As per the 2009 review from Rucklidge and colleagues [2] (someone who knows a thing or two about supplements and ADHD) the jury is still out about G. biloba and it's possible effect with ADHD mind. Certainly, there are quite a few other candidate 'nutrient supplements' which seem to be performing quite a bit better than this herb (see here and see here for example).

That being said, I'd be interested to see what future research has to say about the usefulness of G. biloba with ADHD in mind, specifically from the angle of an adjuvant (add-on) treatment alongside more traditional pharmacotherapy. Again, I say this without in any way, shape or form 'promoting' such use at the current time and with the understanding that management of ADHD is likely to require quite a holistic approach.

Music: The Foo Fighters (who should be at the SoL anytime.... now).

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[1] Shakibaei F. et al. Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complement Ther Clin Pract. 2015 Apr 18. pii: S1744-3881(15)00029-8.

[2] Rucklidge JJ. et al. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev Neurother. 2009 Apr;9(4):461-76.

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Shakibaei F, Radmanesh M, Salari E, & Mahaki B (2015). Ginkgo biloba in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. A randomized, placebo-controlled, trial. Complementary therapies in clinical practice PMID: 25925875

Chronic fatigue syndrome by ASIA?

Unicorns, I love them. Unicorns, I love them. 

ASIA, in the context of this post, does not refer to the continent but rather the suggestion of an: ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ and some potentially contentious findings reported by Nancy Agmon-Levin and colleagues [1].

Describing a small cohort of participants diagnosed with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM), the authors put forward the idea that "some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome", more specifically following hepatitis B vaccination (HBVv). They report on a latency period (the interval between exposure and clinical appearance of symptoms) ranging "from days to a year" with a mean temporal period of around 38 days. They also report specific manifestations of symptoms (neurological, fatigue, muscoskeletal and gastrointestinal) and importantly that: "Autoantibodies were detected in 71 % of patients tested". Autoantibodies by the way, refers to antibodies against self tissue as per what has been noted in various autoimmune conditions/diseases. The authors conclude: "ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM."

OK. There are a few words of caution that one needs to exercise with this kind of work before anyone gets too enthusiastic. This was an information-gathering study, so authors were specifically describing their cohort of participants "following HBVv immunization". There were no control groups, so one also needs to be aware of that.

A quick trawl of the other research literature on the topic of ASIA reveals however that this is not the first time that this concept has cropped up in the peer-reviewed science sector. Shoenfeld &Agmon-Levin [2] (the same authors on the current paper) first advanced the concept of ASIA or [Yehuda] Shoenfeld's syndrome a few years back. Based on the examination of four conditions: "siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena" they concluded that some commonalities were present and ASIA was born. An editorial accompanying their paper [3] kinda said it all: "It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations". I might also direct you to other discussions titled: What is ASIA?

Since then, a number of articles have appeared discussing ASIA / Shoenfeld's syndrome. Bassi and colleagues [4] reported findings involving a mouse model of lupus - "a lupus-prone murine model" - injected with complete Freund's adjuvant (CFA) (an immunostimulant). They reported that: "the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling 'ASIA' syndrome in humans." A more thorough review of the animal model findings can be found in the article by Cruz-Tapias and colleagues [5].

The types of adjuvant noted as being potentially connected to ASIA have also been discussed, as per the article by Vera-Lastra and colleagues [6]. Squalene, aluminum hydroxide and silicone are mentioned. Squalene with regards to Gulf-War syndrome was something which particularly stuck out to me given my previous interest in this collection of symptoms present for some post Operation Desert Storm (see here). Although the source of some speculation, papers such as the one from Pamela Asa and colleagues [7] noting that squalene antibodies were linked to the "majority of symptomatic GWS patients" is an interesting finding. For balance, I will also refer you to the paper by Lippi and colleagues [8] standing up for squalene.

The paper from Perricone and colleagues [9] (open-access) brings us back to the involvement of ASIA in the 'mosaic of autoimmunity' and how genetics and environment might merge. The discussions move into various areas including that of anti-phospholipid syndrome (Hughes syndrome) as well as other well-known autoimmune areas (e.g. coeliac disease). Connective tissues disorders also discussed in the Perricone paper also bring in one reason why hepatitis B vaccine was also considered in the starting paper in question, as per the report by Perricone and Shoenfeld [10] and their discussions on hepatitis B vaccine and 'undifferentiated connective tissue disease' as being: "Another brick in the wall of the.. ASIA". Further research has added to such sentiments [11].

As things stand with the body of research detailing ASIA, I don't think that this is a concept we can readily discard as being potentially real and relevant to at least some clinical presentation potentially including CFS/FM. I know to talk adverse effects from vaccination, or their adjuvants, can stir up some heated discussions in some quarters (see here) but even in contentious areas covering something like autism or autistic presentation, science might still have a role to play [12]. I say this reiterating the important value of vaccination as per this CDC infographic.

This is also the second time that I've talked about vaccination and autoimmunity as potentially being linked on this blog as per another contentious paper in another contentious area (see here). It strikes me that there is quite a bit more to do in looking at any possible connection, particularly when one considers that ASIA has been similarly discussed (albeit in case studies) with other biologics in mind [13].

Music: The Ragtime Gals and a certain celebrity..

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[1] Agmon-Levin N. et al. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunol Res. 2014 Nov 27.

[2] Shoenfeld Y. & Agmon-Levin N. 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011 Feb;36(1):4-8.

[3] Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun. 2011 Feb;36(1):1-3.

[4] Bassi N. et al. Induction of the 'ASIA' syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA). Lupus. 2012 Feb;21(2):203-9.

[5] Cruz-Tapias P. et al. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept. Curr Med Chem. 2013;20(32):4030-6.

[6] Vera-Lastra O. et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome): clinical and immunological spectrum. Expert Rev Clin Immunol. 2013 Apr;9(4):361-73.

[7] Asa PB. et al. Antibodies to squalene in Gulf War syndrome. Exp Mol Pathol. 2000 Feb;68(1):55-64.

[8] Lippi G. et al. Vaccination, squalene and anti-squalene antibodies: facts or fiction? Eur J Intern Med. 2010 Apr;21(2):70-3.

[9] Perricone C. et al. Novel pebbles in the mosaic of autoimmunity. BMC Med. 2013 Apr 4;11:101.

[10] Perricone C. & Shoenfeld Y. Hepatitis B Vaccination and Undifferentiated Connective Tissue Disease: Another Brick in the Wall of the Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA). JCR: Journal of Clinical Rheumatology. 2013; 19: 231-233.

[11] Zafrir Y. et al. Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases. Lupus. 2012 Feb;21(2):146-52.

[12] Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.

[13] Barros SM. & Carvalho JF. Shoenfeld's syndrome after pandemic influenza A/H1N1 vaccination. Acta Reumatol Port. 2011 Jan-Mar;36(1):65-8.

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Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, & Shoenfeld Y (2014). Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunologic research PMID: 25427994