Olanzapine, gut bacteria and weight gain in mice

"These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients."

That was the summary statement derived from data published by Andrew Morgan and colleagues [1] (open-access) looking at how some of those trillions of wee beasties which colonise humans and animals (the microbiome) may very well influence response to medicines... at least in mice. The authors' specific focus on one of the important side-effects of taking neuroleptics (antipsychotics) - weight gain - also potentially invites some new research directions when it comes to curbing such an important issue.

I had so many evil plans in the works - the illiteracy beam,
typhoon cheese, robo-sheep...

I want to get one thing straight before I go further into the Morgan results: this is not a post designed to 'bash' pharmaceutics such as antipsychotics. Not many people would really want to spend [part of] their lives taking antipsychotics if they could really help it, but this class of medicines, with all their faults, quite a few by all accounts [2], do provide something of a service in terms of their impact on symptom presentation in certain states/diagnoses and perhaps most importantly, a "decreased mortality" compared with no treatment [3]. That all being said, I'm very much in favour of research getting to the core reasons why a condition like schizophrenia (one of the conditions managed by antipsychotic use) may present in the first place over and above just managing symptoms by pharmacotherapy and/or other means as and when they occur. I think most people would agree with that sentiment. That and ensuring that antipsychotics are not over-used [4].

Back to the Morgan paper which is open-access but for which I'd like to summarise a few salient points before passing further comment:

• This was a mouse study. I'll repeat that: this was a mouse study. Researchers started from the idea that "the commensal microbiome of the mammalian gut in health and disease has become a topic of intense study". I can't disagree with that given my previous ramblings on this topic over the years (see here). The idea that said gut microbiota may play a role in for example, how we metabolise certain foods and medicines, is also gaining popularity as per the notion of pharmacometabonomics [5] coined in part, by a few authors who's work has been previously talked about on this blog (see here).
• So: "After establishing that C57BL/6J mice gain considerable weight while consuming olanzapine" (i.e. a good mouse model) researchers set about searching for evidence that gut bacteria are "necessary and sufficient for olanzapine-induced weight gain". They did find it by the way, based on the weight differences noted in mice raised on a high-fat diet + olanzapine compared with animals raised on a high-fat diet without medication.
• They also looked at "the effects of olanzapine on the gut microbiome" based on the examination of faecal pellets (nice!) and "high-throughput sequencing of the bacterial 16S ribosomal RNA gene". The results again based on the diet + medication compared to just diet suggested that the medication-treated mice presented with a gut bacteria pattern that "has previously been associated with obesity in mouse and human". That and some interesting findings suggesting that: "Gut microbiota composition is correlated with weight gain" bearing in mind that correlation is not the same as causation.
• Finally, another important suggestion from Morgan et al: "olanzapine has direct antibacterial activity in vitro against two bacterial isolates (E. coli NC101 and E. faecalis OGIRF) derived from the mammalian gut." As per other related findings, don't just assume that medicines just have 'one mode of action' as per that listed on the package insert. Indeed other antipsychotics seem to have for example, anti-parasitic activity [6] which may be relevant to another research area of interest (see here).
• The authors conclude that: "In light of evidence that olanzapine has intrinsic antimicrobial activity, we propose that its actions in the gut may be analogous to the chronic low-dose antibiotic regimens used to promote weight gain in livestock." The idea also being that targeting gut bacteria during something like olanzapine therapy might have the potential to 'off-set' side-effects like weight gain as and when it occurs.

Although this is very early-days research focused on mice not people, I am really quite interested in the Morgan results and where they may eventually lead. Weight gain following antipsychotic use is an important side-effect which, according to other research literature [7], can have sometimes profound effects on things like "long-term cardiac safety". Indeed, when one considers that heart health is for example, a sorely under-appreciated area when it comes to something like schizophrenia (see here), one senses that a degree of urgency is perhaps required to replicate the Morgan findings and see whether they translate into human beings also.

Then comes the speculation: is there any way to mitigate the gut bacteria effects that something like olanzapine might have? I note the Morgan study relied on olanzapine being "compounded into high fat (45 kcal%) food" to simulate the oral route of administration. I do wonder whether the same effects would be observed if other administration routes were trialled, say by injection or via transdermal application [8]? Second question: do the results imply that formulating a probiotic or a pill with the bacterial species seemingly affected by olanzapine may be useful in reducing weight gain? I can't readily answer that last question but certainly there are quite a few studies out there looking at gut bacteria and issues like obesity as per my previous chatter on Akkermansia muciniphila (see here) as one example. Finally, and again with mucho mucho emphasis on my blogging caveat about not giving medical or clinical advice, is there any role to play for the not-so-nice-to-think-about intervention that is the poo transplant? I know, I know... it sounds like the stuff of nightmares but more and more, science is coming around to the idea that particularly when your life is on the line as per Clostridium difficile infection, the faecal microbiota transplantation might offer some real hope. And C. diff infection seems to be only the tip of the [possible] intervention iceberg when it comes to our waste matter...

Music to close: and with memories of the very memorable New Year's Eve concert by Queen and Adam Lambert, a familiar tune...

----------

[1] Morgan AP. et al. The Antipsychotic Olanzapine Interacts with the Gut Microbiome to Cause Weight Gain in Mouse. PLoS ONE. 2014; 9(12): e115225.

[2] Young SL. et al. "First do no harm." A systematic review of the prevalence and management of antipsychotic adverse effects. J Psychopharmacol. 2014 Dec 16. pii: 0269881114562090.

[3] Tiihonen J. et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333: 224.

[4] Marston L. et al. Prescribing of antipsychotics in UK primary care: a cohort study. BMJ Open. 2014 Dec 18;4(12):e006135.

[5] Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14728-33.

[6] Goodwin DG. et al. Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. J Parasitol. 2011 Feb;97(1):148-51.

[7] Wang J. et al. Olanzapine-induced weight gain plays a key role in the potential cardiovascular risk: evidence from heart rate variability analysis. Sci Rep. 2014 Dec 9;4:7394.

[8] Aggarwal G. et al. Formulation, in vitro, and in vivo evaluation of matrix-type transdermal patches containing olanzapine. Pharm Dev Technol. 2013 Jul-Aug;18(4):916-25.

----------

Morgan AP, Crowley JJ, Nonneman RJ, Quackenbush CR, Miller CN, Ryan AK, Bogue MA, Paredes SH, Yourstone S, Carroll IM, Kawula TH, Bower MA, Sartor RB, & Sullivan PF (2014). The Antipsychotic Olanzapine Interacts with the Gut Microbiome to Cause Weight Gain in Mouse. PloS one, 9 (12) PMID: 25506936