Mechanism of Action and Benefits of Agomelatine by Prof Malcolm Hopwood

Posted on May 5, 2016

Prof. Malcolm Hopwood is the Ramsay Health Care Professor of Psychiatry at the University of Melbourne. His research areas of interest include psychopharmacology, clinical aspects of mood and anxiety disorders and psychiatric aspects of acquired brain injury and other neuropsychiatric disorders.

Take home messages:

1. Most human functions are regulated by circadian rhythms which are disrupted in depressed patients. Agomelatine is an antidepressant with a unique mechanism of action. Agomelatine is an MT1, MT2 receptor agonist, and 5-HT2c receptor antagonist.

2. A study conducted by Corubble et al. (2011) analysed changes in emotional blunting comparing patients taking Agomelatine or Escitalopram. The rate of patient agreement indicates the impact SSRI’s have on emotional blunting. Patients were given two sentences (My emotions lack intensity and Things I cared about before my illness don’t seem important anymore. The results were as follows:

  • ‘My emotions lack intensity’ – 28% patients on Agomelatine vs. 60% Escitalopram
  • ‘Things I cared about before my illness don’t seem important anymore’ – 16% patients on Agomelatine, vs. 53% Escitalopram

3. The Snaith-Hamilton Pleasure Scale has been developed to measure concepts of Anhedonia. The Martinotti et al. study compared Agomelatine vs. Venlafaxine on the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D) and the Snaith-Hamilton Pleasure Scale. There were no statistically significant differences in mean scores on the HAM-A or HAM-D, but statistically significant differences were evident on the Snaith-Hamilton Pleasure Scale.

Those antidepressants that directly affect serotonin may not produce as positive of result in terms of ultimate hedonic response. Again, I think you need to interpret with caution what it means about Agomelatine. We can’t tell whether it is just not having the same negative effect as other antidepressants or whether it is doing something positive.

4. Prof. Hopwood moves onto discussing a study conducted by Harmer et al. (2011), whereby the effect of Agomelatine of positive affective memory was analysed. The seven day double-blind RCT using Agomelatine 25mg showed an increased recall of positive vs. negative items when compared to placebo (i.e., an enhancement of recalling the positively laden items).

5. Shifting focus onto the ‘more subtle’ aspects of recovery and depression, Prof. Hopwood discusses the notion of self-focus – evaluating stimuli as related to one’s own person. He discusses a study conducted by Fossati et al. (2013) focused on assessing the brain effects of Agomelatine during a self-referential task in Major Depressive Disorder patients by using fMRI after 7 days administration. The results revealed that in MDD patients there was a normalization of VLPFC hyperactivity at 1 week. This suggests (a careful abstraction)

That we are seeing changes in the wiring of self-reflection of patients exposed to Agomelatine. It doesn’t necessarily mean it doesn’t happen with other agents, but that is not the point of this study.

6. Studies that have looked at functional outcomes using scales such as Sheehan disability scale have shown a reduction in disability as early as at 8 weeks with Agomelatine. (Stahl et al., 2010, Zajecka et al., 2010)

7. The Big Picture:

  • Depression remains a frequent cause of disability
  • Current treatments are mainly assessed on a short-term symptomatic response
  • Outcomes on this basis are modest and adherence poor
  • Assessment of broader functional and ‘well-being’ based measures may assist with better long-term outcomes


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