ClinicSpeak: fatigue and depression improved by natalizumab

Fatigue and depression; two symptoms improved by natalizumab #MSBlog #MSResearch #ClinicSpeak

“One of the first things I noticed when I started using high-efficacy therapies, i.e. those DMTs that render the majority of subjects NEDA (no evident disease activity), is that MSers come back after 3-4 months feeling better. What do I mean by feeling better? They often describe the MS ‘brain fog’ lifting, their ‘fatigue evaporating’, ‘having energy’, improvements in ‘mood and anxiety’ and saying ‘I feel normal again’. This is why I refer to these drugs as being transformational. The study below, aptly referred to as the TYNERGY study, confirms these anecdotal clinical observations. When MSers with active MS go onto natalizumab a large number of their negative symptoms improve. I personally don’t think these observations are limited to natalizumab and are also seen with other highly effective therapies. MSers should consider this good news and include these effects in the risk:benefit assessment when choosing a DMT.”

“How does an an anti-inflammatory like natalizumab reduce fatigue? I think it works via suppressing inflammation in the brain that drives fatigue. Inflammation is known to cause sickness behaviour, a programmed behaviour that is designed to conserve energy and allow the body to recover. Sickness behaviour goes far back in the evolutionary tree so it must have given our evolutionary ancestors a survival advantage. Two mediators of inflammation called interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha) trigger a behavioural response that causes fatigue, hypersomnolence (sleepiness), reduced appetite (anorexia), a raised body temperature (fever) and low mood (depression) that forces us to lie down, sleep and allow our sick bodies to recover. Sickness behaviour is typical of the symptoms we get when we have a systemic infection similar; e.g. how you feel when you have influenza. We know that in MS both IL-1 and TNF-alpha are increased in the brains of MSers. Therefore, I am pretty sure as DMTs switch off inflammation in the brain and IL-1 and TNF-alpha levels drop fatigue improves as sickness behaviour disappears. The following is a slide presentation of one of my recent talks on fatigue that includes a section on sickness behaviour. Some of the point covered in this slide presentation are quite technical; if they need more explanation I am prepared to additional posts on this.”

Penner et al. Improvement in Fatigue during Natalizumab Treatment is Linked to Improvement in Depression and Day-Time Sleepiness. Front Neurol. 2015 ;6:18. doi: 10.3389/fneur.2015.00018. eCollection 2015

BACKGROUND: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing-remitting MSers showed a clinically meaningful decrease in fatigue over 1 year of treatment with natalizumab.

OBJECTIVE: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness.

METHODS: MSers were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of the two latter symptoms and changes in fatigue was analyzed.

RESULTS: After 1 year of natalizumab treatment, the majority of MSers (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of MSers without depression increased by 17% while proportions of mildly depressed MSers or MSers with potential major depression decreased by 5 and 12%, respectively. Proportion of MSers classified as not being sleepy increased by 13% while proportions of sleepy and very sleepy MSers decreased by 11 and 2%, respectively. Most importantly, improved depression and sleepiness were significantly related to improved fatigue.

CONCLUSION: Our findings highlight the importance of patient-reported outcomes in identifying potential benefits of drug treatment beyond its well-established effects on disease activity and disability progression.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Please could you give further explanation of Slide No 32 – the one with the graphs on SR Fampridine. What was being measured – was it just walking ability or was fatigue one of the measured outcomes as well?

    • Re: "Please could you give further explanation of Slide No 32."

      This slide refers to an improvement in walking speed relative to baseline. This does not refer to mental fatigue. It is covered in the talk as motor fatigue, i.e. a drop off with walking distance and speed with exercise and/or rise in body temperature, is a type of fatigue.

    • Thanks Prof G
      I should have been clearer in my question – I did mean "motor" fatigue not mental fatigue. My leg function/coordination and walking speed get worse quite quickly e.g. after about 100-150 metres, even if I am freezing cold. A "heat wave" of any weather temperatures higher than about 23 or 24 Celsius also has a very significant impact. Recently started SR-Fampridine so we'll see what happens. Apart from occasional "can't find the words" moments and a few very short term memory problems I am so lucky to have not suffered any real impacts (yet) on mental function or mental fatigue, and I genuinely feel for those who do.

  • Ah, thank you for this. The 'sickness behaviour' thing makes so much sense to me. I often feel ill but have no actual symptoms of an infection. I get random low moods too. My only caution would be to check iron levels. Have recently found out I'm anemic and chronic anemia is commonest in women of child bearing age, the same group where MS is most prevalent. It's so easy to put everything down to MS. I hope Tecfidera does similar things to inflammation as Tysabri as I've just started taking the former.

  • I am not that impressed with the numbers here ( 2% fewer patients in the "very sleepy" group – statistically significant, but clinically … well, not so much? Plus the authors seem to repeat themselves even in this very short abstract section ( proportion of patients without depression increased … by the same % as the number of mildly depressed and potentially depressed decreased :-). The next sentence is along the same lines, tautology squared. 😉

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