Prenatal nicotine exposure and offspring schizophrenia?

"Another reason why pregnant women shouldn’t smoke: schizophrenia" went one media headline reporting on the findings by Solja Niemelä and colleagues [1] who concluded that their results were the "most definitive evidence to date that smoking during pregnancy is associated with schizophrenia."

Analysing data from nearly 1000 people identified with schizophrenia whose information, and that of their mothers, were held in one of two databases - the Finnish Prenatal Study of Schizophrenia and the Finnish Maternity Cohort - researchers embarked on a case-control study. Maternal cotinine levels - a metabolite of nicotine - were analysed from archive serum samples taken during pregnancy ("early- to mid-gestation") and compared across groups based on offspring who did or did not go on to receive a diagnosis of schizophrenia. Authors concluded that: "A higher maternal cotinine level, measured as a continuous variable, was associated with an increased odds of schizophrenia." The increased 'risk' of offspring schizophrenia to those mothers with the highest cotinine levels (highest nicotine exposure) was somewhere in the region of 38% and "were not accounted for by maternal age, maternal or parental psychiatric disorders, socioeconomic status, and other covariates."

Accepting that correlation is not the same as causation and that one has to be slightly careful when analysing just one biomarker, I was intrigued by these latest findings. A quick trawl of the research literature in this area suggests that this is not the first time that maternal smoking behaviour might have implications for offspring risk of schizophrenia [2]. I don't doubt however, that any relationship is likely to be complicated and potentially influenced by various other factors as we are reminded that elevated levels of maternal cotinine indicative of heavy smoking were also reported in nearly 15% of mothers of control (not schizophrenia) participants in the Niemelä study. I might also add that when it comes to other labels not necessarily a million miles away from schizophrenia, the suggestion of a link with smoking during pregnancy is not strong at all (see here).

Where perhaps the latest findings are so interesting is the idea of a possible relationship between a proxy measure for foetal nicotine exposure and risk of schizophrenia. The emphasis is on 'nicotine exposure' and not necessarily the myriad of other toxins that are present when tobacco combusts (although I'm sure they might exert some kind of effect) thus potentially suggesting that quite a bit more research is indicated on other sources of nicotine exposure during pregnancy such as the use of nicotine replacement skin patches or even e-cigarettes. Indeed, having recently watched the ever-intrepid Dr Michael Mosley discuss the question: 'Are e-cigarettes really a menace?', with the Niemelä findings in mind, one might have to conclude, very possibly if used during pregnancy depending on what level of nicotine they might deliver. Just however, to confuse you further, the use of nicotine - "targeting nicotinic and nicotinic receptor subtypes" [3] - as a potential intervention for [some] schizophrenia has to be mentioned although perhaps not necessarily in the long-term.

Irrespective of the plausibility or generalisability of the Niemelä findings, giving up smoking when pregnant to protect the developing foetus from potential schizophrenia or lots of other things, really is a no-brainer...

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[1] Niemelä S. et al. Prenatal Nicotine Exposure and Risk of Schizophrenia Among Offspring in a National Birth Cohort. American Journal of Psychiatry. 2016. May 24.

[2] Stathopoulou A. et al. Prenatal tobacco smoke exposure, risk of schizophrenia, and severity of positive/negative symptoms. Schizophrenia Research. 2013; 148: 105-110.

[3] Featherstone RE. & Siegel SJ. The Role of Nicotine in Schizophrenia. Int Rev Neurobiol. 2015;124:23-78.

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Niemelä, S., Sourander, A., Surcel, H., Hinkka-Yli-Salomäki, S., McKeague, I., Cheslack-Postava, K., & Brown, A. (2016). Prenatal Nicotine Exposure and Risk of Schizophrenia Among Offspring in a National Birth Cohort American Journal of Psychiatry DOI: 10.1176/appi.ajp.2016.15060800

Delivering medicines in psychiatry the transdermal way: application to autism

The real iron man

Pharmaceutical technology, and specifically the various research strategies looking at the way that medicines are delivered to the body, is probably not a topic high on most people's list of interests. This area is generally not 'sexy' research insofar as producing headlines about almost miracle interventions for condition X or label Y. Instead, we take for granted that the tablet or capsule we have been given has been formulated and tested or that the nicotine patch that you may be wearing includes some pretty comprehensive physics, chemistry and biology behind its development.

In order to raise the profile - even champion the role - of pharmaceutical technology, I'm briefly bringing the paper from Jonathan Stevens and colleagues [1] to your attention, reviewing the literature "related to transdermal delivery systems from the perspective of clinical practice and research related to their use in the treatment of psychiatric conditions." Transdermal delivery by the way, refers to the various ways and means that medicines can be formulated to pass through the skin and into general circulation. This method has significant advantages insofar as bypassing the gastrointestinal (GI) tract and the first pass effect among other things. This might also be important from the point of view of those trillions of wee beasties that call our gut home [2].

I've covered some of the ways and means that transdermal drug delivery might impact / has impacted on conditions like autism before on this blog. This has included the very preliminary suggestion that transdermal nicotine patches might impact on individual cases of aggression comorbid to autism (see here) and some of my own research (see here) looking into the now controversial suggestion that dermal preparations of low dose naltrexone might be useful for various conditions [3].

Insofar as some of the other research talking about transdermal preparations and autism, there are a few studies to quickly direct you towards. The trial by Kern and colleagues [4] is worth mentioning in view of their use of transdermal glutathione with autism in mind and effects "improving some of the transsulfuration metabolites." Glutathione is something of an elephant in the room when it comes to at least some cases of autism (see here). There is also the older study by Fankhauser et al [5] to consider, describing the use of transdermal clonidine in cases of autism. I'm not necessarily advocating clonidine for autism (despite there being some indications for some use) but what this research does suggest is that various medicines currently used to manage some core and peripheral aspects of autism are perhaps ripe for re-formulation in order to better control drug delivery and potentially increase important issues such as compliance to specific medication  regimes. Dare I also mention the use of transdermal secretin [6] when it comes to autism too?

I do think we are going to see more and more about transdermal drug delivery systems being used when it comes to autism and beyond in future times. Coupled to other drug delivery methods such as via the nasal route (think oxytocin and autism... carefully) and the days of pill-popping and even painful injections (all hail micro-needles) may well be numbered.

Music: The Cure - Boys Don't Cry. Well, only at the football (soccer) match and/or when watching Watership Down.

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[1] Stevens JR. et al. The Use of Transdermal Therapeutic Systems in Psychiatric Care: A Primer on Patches. Psychosomatics. 2015 Apr 1. pii: S0033-3182(15)00060-2.

[2] Swanson HI. Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry? Drug Metab Dispos. 2015 Aug 10. pii: dmd.115.065714.

[3] Bouvard MP. et al. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res. 1995 Oct 16;58(3):191-201.

[4] Kern JK. et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011 Dec;17(12):CR677-82.

[5] Fankhauser MP. et al. A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry. 1992 Mar;53(3):77-82.

[6] Ratliff-Schaub K. et al. Randomized controlled trial of transdermal secretin on behavior of children with autism. Autism. 2005 Jul;9(3):256-65.

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Stevens, J., Justin Coffey, M., Fojtik, M., Kurtz, K., & Stern, T. (2015). The Use of Transdermal Therapeutic Systems in Psychiatric Care: A Primer on Patches Psychosomatics DOI: 10.1016/j.psym.2015.03.007

Transdermal nicotine for aggression comorbid to autism?

The paper from Gerrit Van Schalkwyk and colleagues [1] caught my eye recently and a potentially interesting case report on the use of "transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD [autism spectrum disorder]."

Transdermal, by the way, refers to passage through the various and complicated layers of the skin, and reflects an important way of getting medicines into the body other than via the more traditional oral route. I'm more than a little interested in the various ways and means that science is coming up with to bypass the mouth - gut - general circulation route as per other discussions on this blog (see here) with some of my own peer-reviewed contributions in mind [2]. In terms of how this might translate into autism and beyond, think about the processes for example, involved in swallowing a tablet or capsule and whether more could be done to 'ease' the mechanics of getting medicines into the body as well as improving things like adherence to a particular regime...

Anyhow, Van Schalkwyk et al reported that transdermal nicotine use - "a 21 mg nicotine patch" - seemed to have something of a positive effect on aggression in their particular case. Said young man presented with various issues with aggression against himself ("headbanging and biting... continuously re-opened old wounds") and others ("violently attacked staff at school") in the context of "a diagnosis of non-verbal ASD... requiring support with each of his activities of daily living." Various behavioural and pharmacological options were tried to alleviate aggression when he was hospitalised with seemingly little effect.

The idea to use a nicotine patch stemmed from some previous research interest from some of this authorship group on a role for nicotinic acetylcholine receptors in relation to mood and anxiety [3]. Their idea that: "smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders" potentially taps into some interesting research questions on the role of smoking in light of diagnoses where 'affective disorders' may be prominent.

Further research is of course indicated as to whether nicotine patches may be useful for some people and some behaviours associated with the autism spectrum. I say this bearing in mind that the rates of tobacco smoking tend to be quite a bit lower in autism compared with the general population [4] and the desire not to see such figures increase bearing in mind the adverse effects smoking can have for a person. Remember also, that nicotine is classified as addictive...

Music: The Clash - Complete Control.

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[1] Van Schalkwyk GI. et al. Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder. JADD. 2015. May 16.

[2] Dodou K. et al. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. 2014 May 2.

[3] Picciotto MR. et al. Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology. 2015 Jan 9. pii: S0028-3908(14)00479-1.

[4] Bejerot S. & Nylander L. Low prevalence of smoking in patients with autism spectrum disorders. Psychiatry Res. 2003 Jul 15;119(1-2):177-82.

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Van Schalkwyk, G., Lewis, A., Qayyum, Z., Koslosky, K., Picciotto, M., & Volkmar, F. (2015). Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-015-2471-0