Evidence-Based Pharmacotherapy of Generalised Anxiety Disorder: Focus on Agomelatine

Abstract

Recent network meta-analyses support the use of pharmacotherapy in patients with generalised anxiety disorder (GAD). Compared with placebo, drug treatment can improve symptoms and quality of life, and is more effective in preventing relapse. Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors are generally considered the first-line agents of choice in GAD, but in some patients, an alternative evidence-based treatment with a different mechanism of action may also be considered (e.g. those with severe GAD, inadequate response, adverse effects and/or contraindications). One example is agomelatine, a melatonin receptor agonist and serotonin 2C (5-HT 2C ) receptor antagonist, which has been shown to have efficacy that is greater than placebo in patients with GAD, and to have a tolerability profile that compares favourably with that of escitalopram. Both agomelatine and escitalopram are efficacious in treating patients with GAD, including those with severe symptoms. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01860-1.

Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action

“…49 – 51 The positive outcome of these respective studies was recently reprised by a pooled meta-analysis that underpinned evidence for robust efficacy both in alleviating symptoms and in enhancing global patient function. 27 , 28 Efficacy of agomelatine was comparable to the active control, escitalopram (an SSRI), and secondary analysis supported effectiveness in severe GAD (Hamilton Anxiety Scale > 21). 28 , 49 – 52 Although its precise onset of efficacy remains to be further characterized, clinical studies suggest activity within the 1–3 weeks after commencing administration in at least some patients.…”

“… 26 Potential therapeutic efficacy in GAD was subsequently assessed within the framework of controlled clinical trials over 2008 to 2018, and these observations constitute the basis for a dossier in preparation for submission to the appropriate Health Authorities. 27 , 28 These observations are consecutively summarized below and then its potential mechanisms of action are considered in greater detail.…”

“…This represents an important gain over SSRIs and SNRIs – and may also be an advantage compared with buspirone. 13 , 22 , 23 , 27 , 28 , 57 – 62 …”

“…This represents an important gain over SSRIs and SNRIs -and may also be an advantage compared with buspirone. 13,22,23,27,28,[57][58][59][60][61][62] Activation of 5-HT 2C receptors, for example, on hypothalamic proopiomelanocortin neurons, suppresses appetite. Conversely, 5-HT 2C receptor blockade, in particular when coupled to histaminergic and/ or muscarinic receptor antagonism, is a risk factor for increased food consumption, obesity, and metabolic dysregulation, as seen with numerous tricyclic antidepressants and 'atypical' antipsychotics like olanzapine.…”

“…22,28,70,71 To recap, then, the distinctive 5-HT 2C antagonist/ MT agonist receptor-binding profile of agomelatine can be related both to its therapeutic efficacy in GAD and to its good tolerance. 13,27,28,58 Its favourable clinical profile was recently underscored in two separate meta-analyses of a diversity of agents clinically evaluated for the treatment of GAD. 13,58 Nonetheless, for a more fine-grained and complete understanding of the mechanisms of action of agomelatine in the control of GAD, it is instructive to consider a suite of observations acquired mainly in rodents.…”