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Dreaming of Melatonin

Ask any person with children, irrespective of the presence of autism, what are the toughest things about raising a child and I bet many will list a lack of sleep in the early years as being fairly close to the top of their list. Gone are the heavenly 8-hour slumberthons that were taken for granted each night. Replaced instead by 1-2 hours, then 2-3 hours, etc. working up to a full night by about a year (if you are lucky) and even then not in uniform stages. Weekend lie-ins? Yeah, right.

Sleeplessness is not something that the mind and body ever really gets used to. The yearning for sleep when we don’t have enough of it demonstrates how powerful a thing sleep deprivation can be, and how it can impact on so many different parts of waking life.

Think then to how a child who suffers sleeping problems might also feel as a result of consistently disturbed, unrefreshing, qualitatively poor sleeping patterns. Where the internal body clock somehow just does not seem to keep time with the environment around them and the time spent in the land of nod is limited. Think about what impact this might have on the developing body and brain and how irritability, non-compliance, and inattention during waking hours at home and school (the so-called ‘challenging behaviours’) might potentially come about as a result.

There is quite a lot of published evidence to suggest that children diagnosed with an autism spectrum disorder are more likely to be affected by issues with sleep. So for example, presenting with shorter overall sleep time, less REM sleep, more incidents of night-waking, and indications of disordered circadian rhythms when compared to asymptomatic and developmentally delayed controls have all been mentioned. You can perhaps see how all that might cause quite a bit of stress and anxiety both to the child and their parents if delivered over a sustained period of say, months or even years.

The questions then: what causes such sleeping problems in relation to autism and what can be done about it?

Unfortunately there are no cut-and-dried answers; only fragments of information which potentially point to many different mechanisms potentially being involved and with an all too familiar theme, variability in the mode of action across the autism spectrum. Realising that comorbidity such as attention-deficit hyperactivity disorder (ADHD) can, and does, exert an effect on sleeping patterns is also worth mentioning.

What can be done about it? Again, the blueprints for ‘making sure all children with autism sleep all night’ seem to be a work in progress. One strategy however is gaining important ground at least for some children on the spectrum: N-acetyl-5-methoxytryptamine or just plain, melatonin.

Perhaps an introduction first?

Melatonin is an interesting compound synthesized in the pineal gland from another interesting compound, serotonin (5-HT). Many people will have heard about serotonin as a neurotransmitter and its important effects on things like mood; realising also that serotonin has been mentioned quite a few times in relation to autism down the years. The intermediate compound bridging the gap between serotonin and melatonin, N-acetylserotonin (NAS), is itself something also which could really do with a lot more investigation given some preliminary suggestion of an anti-depressant effect among other things.

So what’s the story with regards to autism and melatonin?

Well, quite a bit. Generally speaking, levels of circulating melatonin and some of its metabolites have been noted to be on the low side in cases of autism as per the excellent meta-analysis by Drs. Rossignol and Frye [1]. Even more recent research [2] looking at both daytime and night-time levels of the main metabolites of melatonin, 6-sulphatoxymelatonin, confirmed issues with melatonin production to be present in cases of autism. Interesting also was the suggestion of a link between production issues and degree of symptom severity by Tordjman and colleagues; as in the more severe the autism, the more profound the issues with melatonin.

Why might melatonin production be aberrant in cases of autism?

The big question-and I’m afraid that I don’t have a big answer. There are a few possibilities: issues with the pineal gland or suprachiasmatic nucleus (the master clock centre), issues with serotonin or the starting material tryptophan, issues with the various reactions involved in the metabolism of melatonin (or precursors)… take your pick, bearing in mind this list is not exhaustive.

I find it particularly interesting that (a) there might be a sensory-perceptual link to the production of melatonin which might be related to melatonin issues in some cases of autism, and (b) acetylation and methylation are required steps in the metabolism of melatonin. I might be making mountains out of molehills but it strikes me that some people on the autism spectrum aren’t exactly flush when it comes to activities such as methylation. Just speculating of course.

Supplementation?

With the very important caveat about not giving medical advice, melatonin does seem to have quite a good record when it comes to at least some cases of autism spectrum disorders and a few other diagnoses. Sleep and the regulation of sleep is the obvious target of melatonin, which itself can have some pretty important influence on presented behaviour as previously mentioned.

Two quite recent trials extended the good news about melatonin: one from Malow and colleagues [3] and another from Cortesi and colleagues [4]. I was particularly interested in the ‘controlled-release’ bit of the work presented by Cortesi given the mechanics of variations in endogenous melatonin production. It strikes me that melatonin is an ideal candidate for some of the newer release technologies being looked at in the world of medicines; such that transdermal patches and the like might have something valuable to offer as per other formulations and trials.

Having said all that, and bearing in mind that lots and lots of different ‘medications’ have probable biological actions outside of those just intended, melatonin might not be just acting on sleep. I recently read an interesting (and again, speculative) review article about melatonin as a molecular ‘handyman’ by Boga and colleagues [5] which does get you thinking about the hows and whys. There are also some other interesting activities of the compound, for example with regards to being an antioxidant [6]. Antioxidants and oxidative stress takes us into a whole other realm with autism in mind (thinking about glutathione for example) so perhaps best to leave that for now.

I think most people realise the importance of sleep and what happens when sleep is at a premium. Sleeping issues when they do arise in cases of autism require some detailed thought about what might be causing them and also understanding of the knock-on effects on behaviour they can have. Melatonin offers one strategy which might offer some help with sleeping issues in cases of autism; realising however the lack of a ‘one size fits all’ in autism and the notion of ‘more than one effect’ in connection to melatonin.

[1] Rossignol DA. & Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology. 2011; 53: 783-792.

[2] Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. May 2012.

[3] Malow BA. et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. JADD. December 2011.

[4] Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. Journal of Sleep Research. May 2012.

[5] Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this “molecular handyman”? Reviews in Medical Virology. April 2012.

[6] Hardeland R. & Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism. 2005; 2: 22

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