Barcelona snapshots

Prof. Catherine Belzung

Catherine Belzung psychiatrist Controversias Psiquiatry Barcelona
Université de Tours, France
Talk Mechanisms underlying antidepressant-resistance in depression
Date Friday, April 26th, 2019
Time 14:30 to 15:15
Round Table Treatment-resistance in affective disorders


Catherine Belzung is the chair of the Inserm research unit "Imaging and Brain" (iBrain, UMR 1253, Tours, France), a multidisciplinary Research Center integrating research in Psychiatry (mainly focusing on autism spectrum disorders and on treatment - resistant depression), studies in cellular/molecular neurosciences and investigations aimed to develop new technologies for diagnosis and treatment of psychiatric disorders (as methodologies relying on radiopharmaceuticals). She is full Professor in Neurosciences, and senior member of the prestigious "Institut Universitaire de France". Her research focuses on preclinical models of depression, with a focus and hippocampal neurogenesis, antidepressant resistance, and more recently, neurostimulation techniques. She is member of several panel (for example ERC Starting Grant) and editorial board of various journals (Behavioural Pharmacology, Neuropharmacology). She authored 175 publications in international peer reviewed journals.


Major depressive disorder (MDD) is a severe mental illness that has become the second leading cause of disability worldwide. MDD patients are treated at first glance with chronic antidepressant drugs such as selective serotonin reuptake inhibitors, which increase monoaminergic neurotransmission in the synaptic cleft in brain areas relevant to the MDD symptomatology. However, up to 50% of individuals with MDD are resistant to conventional pharmacological therapy. So, the question of the mechanisms underlying of antidepressant resistance has become a crucial issue.

Several factors underlying treatment resistance have been described that are listed bellow:
  1. Error in the MDD diagnosis: in case patients suffer from another medical condition sharing symptoms with MDD, patients can be misdiagnosed. Examples are patients exhibiting normal sadness, or patients with bipolar disorder or Alzheimer disorder: the MDD-related symptoms are logically resistant to antidepressants as they might rely on other causes than a defect in monoamines;
  2. Heightened vulnerability to depression, such as the one related to childhood maltreatment for example, or to an history of depression. Childhood maltreatment might produce long lasting changes, such as for example in the white matter, that cannot be targeted by monoaminergic antidepressants. An history of MDD is associated to a specific molecular scare in the brain of the patients, that will not answer to monoaminergic drugs;
  3. Mechanisms relating to the metabolism of the drugs, to their penetration into the brain or to the cascade involved in the drug's action are strongly involved. Patients having polymorphisms of genes coding for proteins necessary to the monoaminergic antidepressant's action, such as for example patients with a polymorphism of the gene coding for the 5-HT transporter. In this case, the molecular target of the molecule might be un-effective in eliciting the molecular changes necessary to the antidepressant's effects. The same applies to other aspects of the cascade involved in the antidepressant action such as for example adult hippocampal neurogenesis;
  4. Patients having a MDD related to neuro-inflammation. In this case, putative treatments should target inflammation instead of monoamines;
  5. Patients with dysfunction of a brain circuit including the anterior cingulate cortex also exhibit treatment resistance. These dysfunctions might respond to neurostimulation of the defected network;
  6. Patients exhibiting specific plasmatic markers also exhibit treatment resistance.
In conclusion, better knowledge of these mechanisms might enable to identify patients that will not respond at a very early stage, and permit to the clinicians to propose alternative treatments at a first glance. This will also enable to design new therapies that will target the abnormalities exhibited by the patients.


[PDF] El-Hage W, Vourc'h P, Gaillard P, Léger J, Belzung C, Ibarguen-Vargas Y, Andres CR, Camus V. (2015). The BDNF Val(66)Met polymorphism is associated with escitalopram response in depressed patients. Psychopharmacology (Berl). 2015 Feb;232(3):575-81. doi: 10.1007/s00213-014-3694-z. Epub 2014 Jul 31.

[PDF] Willner P, Belzung C (2015). Treatment-resistant depression: are animal models of depression fit for purpose?. Psychopharmacology (Berl). 2015 Oct;232(19):3473-95. doi: 10.1007/s00213-015-4034-7. Epub 2015 Aug 21.

[PDF] El-Hage W, Leman S, Camus V, Belzung C (2018). Mechanisms of antidepressant resistance. Front Pharmacol. 2013; 4: 146. Published online 2013 Nov 22. doi: 10.3389/fphar.2013.00146

[book] Wakefield JC, Demazeux S (2016). Sadness or Depression?: International Perspectives on the Depression Epidemic and Its Meaning. Springer; Edición: 1st ed. 2016