Agomelatine but not melatonin improves fatigue perception: A longitudinal proof-of-concept study, Pardini et al, 2014

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rapidboson

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Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties.

To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep–wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition.

Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50 mg u.i.d. with sustained release melatonin 10 mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study.

Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects.

Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.

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Fukuda criteria

I can't see if the study was blinded or not. I'm interested to hear more about the study.

It suggests that melatonin in this dose and formulation is not helpful for (ME)/CFS.
 
On brief inspection it looks quite interesting.

They used Fukuda, but they may still have recruitd mostly ME/CFS patients.

The description of blinding is tortuous but sounds like it was double at least until the swap over for melatonin - which is good enough.

The comparison of melatonin with agomelatine is quite neat because it does seem to show that melatonin does not work, as well as that agomelatine does.

There may be holes that I have missed.

I wonder why it was published in the most obscure journal possible?
 
Here's an excerpt regarding blinding:

Subjects were randomized to receive either agomelatine 50 mg/die (group A) or sustained release melatonin (group B) 10 mg/die for 12 weeks (Dalton et al., 2000). Before the enrollment phase we electronically generated a list of random numbers, which were then consecutively assigned to every subject based on the order of enrollment. Subjects associated with even numbers were included in group A, while subjects associated with odd numbers were included in group B. The random number label for each patient was stored in a closed envelope until the completion of the screening phase, thus enrolling physicians were blind to each phase of the randomization. Moreover, to ensure blinding, the two drugs were matched in appearance.
Socio-demographical, clinical and cognitive characteristics of the two groups are presented in Table 1. At this stage (phase I) both the subjects and the evaluating physicians were blinded to the treatment. Therefore, patients and physicians were blind to the treatment when evaluations at enrollment and after 12 weeks took place. At the end of the follow-up period (week 12), subjects in the melatonin group were switched to agomelatine and re-evaluated after 12 more weeks (i.e. after 24 weeks from enrollment) (phase II).
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They briefly mentioned this paper and a Russian one in the ME/CFS conference in Berlin, I just found the video. From around minute 6:15!



This is the other paper he mentions in his presentation. Observational study on depressive episodes after COVID - includes a 10 point improvement in physical SF-36.
 
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Snow Leopard said:
Seems like more evidence against the use of SSRIs...
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Agomelatine is a serotonin antagonist, blocking serotonin receptors (so presumably reducing its action), whereas SSRIs block serotonin reuptake, (so presumably increasing the effect of serotonin).

Agomelatine appears to be effective in making a range of measures better. The FSS has 9 questions rated 1-7, 63 is the worst fatigue and 9 is the best. So, the reported change is quite considerable Phase 1 56.1 -> 34.9

It looks a bit too good to be true. I wonder if there have been any more studies of it?

BTW, the subjects scored in the normal ranges for the HADS depression and anxiety questionnaires.
 
From what I've been able to gather on agomelatine, it's a bit debated whether it really shows any 5-HT2C antagonism at clinical doses. The ki for the MT receptors are subnanomolar, where the ki for 5-HT2C is an order of magnitude higher.

But apparently MT-2 and 5-HT2C form heterodimers, so that might help with bringing the agomelatine in close proximity to the 5HT2C.
Note, they are using the highest clinically used dose of 50 mg rather than the standard 25 mg.

Antagonism of 5HT2C apparently disinhibits dopaminergic and noradrenergic signalling in the PFC.
 
rapidboson said:
This is the other paper he mentions in his presentation. Observational study on depressive episodes after COVID - includes a 10 point improvement in physical SF-36.
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Fulltext translated from Russian with DeepL.

Prospective observational trial from 2024 of post-COVID depressed patients. Only adding it, as it was mentioned in the talk.
 

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Reduced perception of fatigue is a real double-edged sword if it causes you to go beyond your limits. Even if it's just by a little bit each day, because you feel you're a bit brighter for whatever reason, culminating in a crash. I'd guess a lot of us have been down that dead end at times.
 
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