Minocycline for schizophrenia?

"Minocycline may improve the psychopathology of schizophrenia, especially the negative symptoms, and seems to be well tolerated".

A Bachelors Drawer (apparently) @ Wikipedia 

That was the finding from the systematic review and meta-analysis undertaken by Oya and colleagues [1] looking at the collected literature on the use of "minocycline augmentation therapy in patients with schizophrenia receiving antipsychotic agents". Augmentation therapy by the way, refers to the addition of minocycline to existing pharmacotherapy for schizophrenia.

I wasn't all that surprised to read the Oya paper given that for some time now, there have been scientific rumblings about how antibiotics might do quite a bit more than just 'killing bacteria' [2]. "Scientists shocked" was how one media report has previously talked about this area of research; which conjures up all-manner of visions of stunned science-types walking around with lab coats on and mouths and eyes wide open in amazement.

The reports that minocycline might act on the negative symptoms of schizophrenia (see here) is also quite an important detail, because these are often the symptoms which affect daily living skills, potentially manifesting as "losing interest and motivation in life and activities, including relationships and sex... [and a] lack of concentration, not wanting to leave the house and changes in sleeping patterns". These are also the symptoms which tend to respond less well to traditional management strategies like medication.

The final question(s) are how and why does minocycline affect cases of schizophrenia? The paper from Zhang and Zhao [3] (open-access) provides quite a good overview of the various hypotheses put forward. Unsurprisingly, some effect on inflammation figures quite strongly in the suggestions put forward. I could go on and on and on about the various research in this area (see here for example) but won't on this occasion. Instead, I'll direct you to a previous post I wrote on minocycline and Fragile X syndrome (see here) which mentions some effect from minocycline on matrix metalloproteinase-9 (MMP-9). I'd like to think that this is a potentially important point because of the tie-in with something like homocysteine (see here), the big H, which has also been mentioned with schizophrenia in mind (see here). Just speculatin' of course.

Music to close. Frank Sinatra and something about a lot of coffee in Brazil?

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[1] Oya K. et al. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2014 Aug 4.

[2] Levkovitz Y. et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49.

[3] Zhang L. & Zhao J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014 Jun 17;10:1103-11.

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Oya K, Kishi T, & Iwata N (2014). Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Human psychopharmacology PMID: 25087702

Homocysteine, gut permeability and MMP-9?

A speculative post this one, on the paper by Hao Ding and colleagues [1] (open-access here) looking at how, in a rodent model of colitis, homocysteine (the big 'H') might play some part in aggravating "inflammatory damage" potentially through promotion of some of the matrix metalloproteinases, MMP-2 and MMP-9. The words: "Hcy [homocysteine] can increase intestinal permeability" added to the interest.

If you're used to reading about autism research on this blog, you might be wondering why on earth I've posted about this study. Well, with that pinch of salt at the ready, the Ding study got some of the grey-pinkish matter thinking...

• So, homocysteine and autism. I hope I'm not inflating the collected literature on this topic too much but elevations of Hcy certainly do seem to be quite consistently reported [2] (open-access here) and importantly, spanning various geographies of autism [3] (open-access here). 
• Homocysteine in relation to the MMPs is something new to me but there is quite a body of peer-reviewed work suggesting that Hcy does seem to have an effect on the MMPs, particularly MMP-9 [4] in terms of enhancing MMP-9 production via the ERK (extracellular signal-regulated kinase) pathway. To quote from the Lee paper [4] "MMP-9 expression was concentration- and time-dependently increased by Hcy". MMP-9 is still something which needs exploring when it comes to autism but at least one study has hinted that amniotic fluid levels of MMP-9 when elevated might tie into some elevated risk of subsequent offspring autism [5] (see a previous post on this trial). I might add that MMP-9 levels have also been talked about with ADHD (attention deficit hyperactivity disorder) in mind too (see here).
• Then to the next stage of the speculations... MMP-9 and it's possible relationship with intestinal permeability AKA leaky gut. It seems that MMP-9 might have the ability to affect permeability [6] at least in the laboratory. To quote from Munjal and colleagues: "Hcy instigated HIMEC [human intestinal microvascular endothelial cell] monolayer permeability through activation of MMP-9". Further: "this increased permeability was alleviated by inhibition of MMP-9 activity". Leaky gut and autism y'say? Well, let's just say that there is peer-reviewed science suggesting this phenomenon to be present in at least some cases of autism (see here and see here).

OK, I know there's been speculation a-plenty in this post and by saying all of this I am by no means try to pin everything on homocysteine, MMP-9 or anything else when it comes to autism. I would never be that silly. I would however suggest that there is a study or two to be done based on these speculations, asking questions about whether MMP-9 is truly elevated in some cases of autism, and whether homocysteine levels or gut permeability measures may show some connection to one and another and MMP-9. That also the Ding paper focused on an animal model of acquired colitis, an inflammatory bowel disease, also offers another potential differentiating factor if one is to assume that autism is not protective of any other condition, including those of the inflammatory bowel disease grouping (see here and see here). I could go on further and bring GABA receptors and how use of something like "The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation" [7] (open-access here) but that's perhaps another topic for another day, alongside minocycline [8] or even melatonin [9]. 

I'm quite finished now. Apart, that is, from telling you that You Give Love a Bad Name... (the Bon Jovi song that is, not necessarily you personally).

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[1] Ding H. et al. Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterol Rep (Oxf). 2014 Apr 27.

[2] Kałużna-Czaplińska J. et al.  A focus on homocysteine in autism. Acta Biochim Pol. 2013;60(2):137-42.

[3] Tu WJ. et al. Serum homocysteine concentrations in Chinese children with autism. Clin Chem Lab Med. 2013 Feb;51(2):e19-22.

[4] Lee SJ. et al. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):89-94.

[5] Abdallah MW. et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. 2012 Dec;5(6):428-33. 

[6] Munjal C. et al. Matrix metalloproteinase-9 in homocysteine-induced intestinal microvascular endothelial paracellular and transcellular permeability. J Cell Biochem. 2012 Apr;113(4):1159-69.

[7] Tyagi N. et al. Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway. J Cell Physiol. 2009 Jul;220(1):257-66. 

[8] Dziembowska M. et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013 Aug;161A(8):1897-903. 

[9] Rudra DS. et al. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res. 2013 May;54(4):398-405. 

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Ding H, Mei Q, Gan HZ, Cao LY, Liu XC, & Xu JM (2014). Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterology report PMID: 24787389

MMP-9 and symptom severity of ADHD

"The statistical regression analysis revealed a correlation between increased serum MMP-9 levels and severity of symptoms in the ADHD". That was the sentence that caught my eye taken from the paper by Halina Kadziela-Olech and colleagues [1] (open-access here) looking at serum matrix metalloproteinase-9 (MMP-9) levels in children with hyperkinetic disorder (HKD) [2] "a severe form of a syndrome which is referred to in DSM-IV... and the American literature as attention deficit hyperactivity disorder (ADHD)".

Hamlet @ Wikipedia 

MMP-9 is something that has already been talked about on this blog with autism in mind (see here) but basically refers to a protease which is involved in degrading proteins of the extracellular matrix [3] and other duties. As Kadziela-Olech et al  point out, there is some preliminary interest in MMP-9 with reference to "neuropsychiatric disorders" particularly with schizophrenia in mind [4]. Interestingly also is that quite a bit of the conversation about MMP-9 and its potential effects have focused on the blood-brain barrier [5] under certain circumstances, which is something that I've always been more than a little interested in (see here) particularly transport across this important barrier.

Anyhow, back to the paper in question:

• Analysis was conducted on 37 boys with HKD/ADHD all properly assessed, as were cognitive functions (via the WISC-R). Blood samples were donated and MMP-9 activity assessed by ELISA (see here).
• Results: bearing in mind there was no asymptomatic control group, it's pretty pointless for me to talk about the serum levels of detected MMP-9 in cases overall. Of more relevance were the various associations made between levels of MMP-9 and presented symptoms: "The MMP-9 levels were significantly associated with symptoms severity of HKD and of ADHD".
• In particular, MMP-9 levels seemed to correlate best with the impulsivity symptom domain when it came to HKD.

In the paper discussion, the authors do go through some of the possible ways that MMP-9 might relate to ADHD/HKD. Part of those discussions focus on blood-brain barrier (BBB) permeability and whether some of the reported risk factors for ADHD may affect MMP-9 expression onwards to a sort of 'leaky' BBB (sounds very familiar). I note also mention of minocycline as a MMP-9 inhibitor (see here) which may very well tie back into some of the research work being done with autism / Fragile X syndrome in mind, particularly given the overlap being reported between diagnoses like autism and ADHD. Some light reading around the topic of MMP-9 also reveals that there may be lots of other functions/relationships to had for this protease. With my cherry-picking hat on, I note the paper by Rodrigues and colleagues [6] talking about inflammation and in particular: "MMP-9 expression in the colon causes alterations in the fecal microbiome" given my interest in all-things gut microbiomics.

Ultimately however, quite a bit more work needs to be done in this area before anyone gets too carried away. Bearing in mind the Kadziela-Olech study was a snapshot study and as I said, without relevant control groups, there are some limitations on what can be said about the findings. Looking also at the plots correlating behavioural presentation and MMP-9 levels it's quite obvious that the relationship between the two variables is not altogether straight-forward despite what the statistics might suggest.

But don't let that deflect from their findings and the need for more research in this area...

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[1] Kadziela-Olech H. et al. Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. Eur Child Adolesc Psychiatry. 2014 Mar 17.

[2] Cameron M. & Hill P. Hyperkinetic Disorder: Assessment and Treatment. Adv Psychiatr Treat. 1996; 2: 94-102.

[3] Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197-250

[4] Yamamori H. et al. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett. 2013 Nov 27;556:37-41.

[5] Li YJ. et al. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels. J Neuroinflammation. 2013 Jul 5;10:80.

[6] Rodrigues DM. et al. Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis. BMC Microbiol. 2012 Jun 13;12:105.

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Kadziela-Olech H, Cichocki P, Chwiesko J, Konstantynowicz J, & Braszko JJ (2014). Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. European child & adolescent psychiatry PMID: 24633733

All eyes on minocycline

Minocycline, the tetracycline antibiotic, is probably not something that most people would traditionally link with autism or conditions presenting with autism-like behaviours. Indeed, the suggestion that antibiotics or antimicrobials if you prefer, may be able to modify either the behaviour or linked biochemistry of the autism spectrum disorders (ASDs) or even influence the onset and expression of ASD is quite frankly a little bit unusual.

Minocycline (for chemists) @ Wikipedia  

But unusual is what often crops up on this blog. And how if one assumes that autism, sorry the autisms, are not just conditions solely pertaining to the grey-pinkish matter floating inside our skull, one starts to see how behaviour and physiology might provide some interesting perspectives. Say for example, when one starts to look at the gut microbiome...

On today's post I'm considering a few reports which recently cropped up on the research radar including the results of placebo-controlled trial of minocycline for Fragile X syndrome (FXS) published by Mary Jacena Leigh and colleagues* (open-access), a small open-trial of minocycline reported by Carlos Pardo and colleagues** (open-access) and although not autism-related, the results of a study by Parvin Ataie-Kachoie and colleagues*** (open-access) on what happened to an ovarian cancer cell line when minocycline was added, specifically with the cytokine IL-6 in mind. A bit of a mixed bag of studies by all accounts but with some potential common threads.

The Leigh study has already been covered by some media (see here) so no grand description needed from me. Suffice to say that there is a suggestion from this MIND Institute study, that minocycline might have some modest positive impact on various aspects of behaviour in paediatric cases of FXS with the requirement for further research. As per some previous chatter on this blog, this is not necessarily new news for FXS as per studies like the one by Paribello and colleagues**** (open-access). Interestingly, the Paribello results also mention something called matrix metalloproteinase-9 (MMP-9) as a particular target of minocycline which has also been discussed on this blog (see here). So, potentially (potentially!) there may be some merit in looking at minocycline for cases of FXS; although as per my blog caveat, I'm not recommending anything.

Moving on. The Pardo study (see here for the trial record), whilst small in participant numbers, looked more directly at the use of minocycline - and vitamin B6 - with ten children diagnosed with an ASD. The focus was on autism with a regressive aetiology linked to presentation, and alongside various behavioural measures, there was also analyses of various biological fluids for "markers of neuroinflammation". The study was open and unblinded so not exactly the same calibre as the Leigh trial.

The main result of the trial, er... no clinical improvements following minocycline use, even after six months of use. Indeed not only were no significant changes to behaviour reported but a variety of respiratory and gastrointestinal (GI) side-effects correlated with minocycline use. The efficacy and safety profile was not particularly great based on these study results allowing for the lack of any control group and the dosage used.

There were however, a few reported changes to some of the biochemistry under investigation, specifically with brain derived neurotrophic factor (BDNF) and hepatocyte growth factor (HGF) in mind but not in the more classically related parameters such as that MMP-9 connection. This lack of effect of minocycline on MMP-9 is slightly unusual but potentially revealing. Certainly the review by Siller & Broadie***** (open-access) hints that MMP inhibition might be a key part of the effects of minocycline in FXS. It's possible a few scenarios might pertain with regards to the biological/genetic differences between autism and FXS. One might even speculate that there is some involvement for the TIMPs (tissue inhibitors of metalloproteinases) in that non MMP inhibitory effect noted from minocycline in autism, but much more work is perhaps needed.

Indeed the authors very overtly noted that "minocycline exerted biological effects that were not translated into behavioral or neurological changes" which certainly questions the link between some of the biochemistry that was seemingly affected and presented symptoms assuming there wasn't more subtle behavioural changes.

Finally, there is the Ataie-Kachoie study on minocycline application to ovarian cancer cell lines. I'll freely admit that I know even less about cancer cell lines than I do about autism so please excuse any widely inaccurate statements that I might make. The long-and-short of it was that in the lab, minocycline seems to have an interesting effect on "the IL-6 signaling pathway" at least in ovarian cancer cells such that minocycline might reduce IL-6 or at least prevent increases after certain events. As part of my learning jounrney through this paper I did not know that IL-6 was for example being linked to cancer metastasis as discussed by Tawara and colleagues****** for example. Seemingly this metastasis might correlate with those MMPs (particularly MMP-2 and MMP-9).

I know I'm moving further and further away from my autism and FXS purpose with the Ataie-Kachoie data, but there may be some lessons to be learned. That for example minocycline might affect cases of FXS by means of impacting on MMP-9 is already under discussion. The added suggestion that minocycline might also be working on cytokines like IL-6 in an anti-inflammatory fashion is certainly another source of discussion. Indeed, I note from the Pardo autism study, that in Table 3 showing the pre- and post-treatment effects on biochemistry, the value reduction for serum IL-6 just managed to escape that magical significance point coming in at p=0.08. The change in another interesting cytokine, TNF-alpha, was even closer (p=0.074).

This has been a post comparing apples and pears to a large extent and reiterating my earlier caveat, I am by no means advocating minocycline for anything other than it's intended use with appropriate medical physician support and supervision. Outside of the discussions already included, what this post does serve to show is that (a) the actions of medicines are not necessarily restricted to what's printed on the patient information leaflet, and (b) some of those 'extra' actions might yet hold some promise for some presenting with autism or autism-like behaviours across the autisms and indeed other conditions.

To close, while recently watching the excellent film 'The Sting' I was again entranced by the piano genius of Scott Joplin's 'The Entertainer'.

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* Leigh MJ. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with Fragile X Syndrome. J Dev Behav Pediatr. 2013; 34: 147–155.

** Pardo CA. et al. A pilot open-label trial of minocycline in patients with autism and regressive features. Journal of Neurodevelopmental Disorders 2013: 5: 9.

*** Ataie-Kachoie P. et al. Minocycline suppresses Interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: In Vitro and In Vivo studies. PLoS ONE. 2013; 8: e60817.

**** Paribello C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010; 10: 91.

***** Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for Fragile X Syndrome. Neural Plasticity. 2012; 124548.

****** Tawara K. et al. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Management & Research. 2011; 3: 177-189.

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Leigh, M., Nguyen, D., Mu, Y., Winarni, T., Schneider, A., Chechi, T., Polussa, J., Doucet, P., Tassone, F., Rivera, S., Hessl, D., & Hagerman, R. (2013). A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome Journal of Developmental & Behavioral Pediatrics, 34 (3), 147-155 DOI: 10.1097/DBP.0b013e318287cd17

Matrix metalloproteinases and autism

Peptidases. The enzymes that split apart peptide bonds, have always been of some interest to me. Not only resulting from my continued interest in peptides as being one potential suggestion why a gluten- and/or casein-free diet might affect symptom presentation in some cases of autism but also because of their relationship to the building blocks of functional life, the amino acids, which are really starting to make some waves in autism research.

Just split @ Wikipedia  

With all this in mind, it was perhaps inevitable that I would arrive at a post on a specific class of peptidases, the matrix metalloproteinases (MMPs) and some very preliminary suggestions of potential involvement in cases of autism and beyond. Please note that not all peptidases work on the same types of peptides, just in case you wondered.

It was the paper by Abdallah and colleagues* which spurred me into writing this post, and their suggestion that analysis of amniotic fluid samples indicated that levels of MMP-9 were elevated in cases later diagnosed with an autism spectrum disorder (ASD). The fact that they also mentioned BDNF was a bonus interest.

Perhaps I should back up a little and provide a quick overview of the MMPs. So with my Twitter limit: zinc-dependent, embryonic development, removal of extracellular matrix, immune function and inflammation, synaptic plasticity**, etc. There are a number of very good review articles on the MMPs including this one by Birkedal-Hansen and colleagues*** (open-access).

The specific MMP discussed by Abdallah et al, MMP-9, has been the topic of quite a lot of research interest over the years. The degradation of collagen is an obvious starting point for all the MMPs, hence a link with connective tissue disorders such as rheumatoid arthritis**** (open-access). It is however with the brain and various neuropsychiatric conditions in mind, that I find myself drawn to the potential effects of MMP-9.

Domenici and colleagues***** (open-access) for example, reported on the possibility that elevated plasma MMP-9 levels may (alongside other compounds) be a biomarker for depression in their cohort. Indeed the genetics of MMP-9 have been similarly linked to bipolar and related disorders. There remains however the chicken-and-egg situation of which came first, MMP-9 or symptoms, not really answered by studies such as this one by Rybakowski and colleagues****** relying on MMP-9 levels to predict staging of bipolar disorder.

Outside of the Abdallah study, there is not presently a great wealth of research done on the MMPs with autism in mind. Accepting the fact that Abdallah was looking in amniotic fluids samples and therefore not functional levels per se, I did turn up this paper by Siller and Broadie******* (open-access) looking at MMPs in Fragile X syndrome (FXS). Regular readers might remember a few papers discussed on this blog in recent times with FXS as the target condition (see here and here) presenting with autistic features. Siller and Broadie asked whether administration of the antibiotic minocycline might actually serve to inhibit MMP (activity or formation?). The answer: it might as per other work in this area but please note that this is not to be construed as medical advice.

I was likewise interested to read the paper by Jang and colleagues******** on how everyone's favourite sleeping aid, melatonin, might also have some important effects on MMP-9 levels, at least in a rat model of stroke. That and the possibility(!) that this relationship might also involve blood-brain barrier (BBB) disruption really got the grey matter working. Once again a pharmacological effect that you won't see on the drug packaging insert.

We have yet to see all there potentially is about MMPs with autism in mind. With all the current interest in excitotoxicity in cases of autism linked to things like glutamate and compounded by the whole microglia story, I'm sure it is a topic that will gain in research popularity and perhaps even open up new avenues for intervention********* for specific people and/or groups should perturbed levels be found and replicated. Given also the possibility of a viral link to elevations in MMP9********** one has to assume that environment may also play a hand in some presentations and potentially tie into those models of maternal infection as being a risk factor for offspring autism?

To finish, the King at his best...

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* Abdallah MW. et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. September 2012.

** Huntley GW. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nature Reviews Neuroscience. 2012; 13: 743-757.

*** Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993 ;4: 197-250.

**** Distler JHW. et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. PNAS. 2005; 102: 2892-2897.

***** Domenici E. et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One. 2010; 5: e9166.

****** Rybakowski JK. et al. Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression. J Affect Disord. August 2012.

******* Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural Plast. 2012: 124548

******** Jang JW. et al. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J Neurol Sci. 2012. pii: S0022-510X(12)00524-2

********* Leonardo CC. & Pennypacker KR. Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation. 2009; 6: 13.

********** Kolb SA. et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid. J Neuroimmunol. 1998; 84: 143-150.

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Abdallah MW, Pearce BD, Larsen N, Greaves-Lord K, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL, & Grove J (2012). Amniotic Fluid MMP-9 and Neurotrophins in Autism Spectrum Disorders: An Exploratory Study. Autism research : official journal of the International Society for Autism Research PMID: 23008271