A multimodal translational approach to explore the role of neuroplasticity in depression and antidepressant treatment: from the bench to the bedside

Depression is a highly prevalent mood disorder that inflicts a heavy burden in depressed patients and a significant social and economic impact worldwide. Nevertheless, the precise physiopathological mechanisms involved in its aetiology and in the therapeutic actions of antidepressant drugs are still largely unknown. Previous studies have implicated different neuroplastic phenomena in the neurobiological basis of depression. In particular, the role of adult neurogenesis in the hippocampus and dendritic and synaptic plasticity in different brain regions in the behavioural actions of antidepressant drugs has been the focus of recent attention in this field of research. In this project, we addressed the behavioural interactions of mood, anxiety and cognition in an animal model of depression, taking into account the neuroplastic events that might underlie the behavioural actions of different antidepressant drugs. On the other hand, in a clinical cohort of drug-naïve patients with Major Depression we explored predictive models for the individual responses to different antidepressant drugs, evaluating the impact of acute administration of antidepressant drugs before and after prolonged antidepressant treatment with functional magnetic resonance imaging (fMRI). In addition, we are conducting different clinical trials, namely a phase 3b clinical trial in patients with treatment-resistant depression and a phase 1 trial in healthy volunteers with an experimental new compound. These complementary fundamental and clinical approaches pave new paths for the comprehension of this complex psychiatric disorder and for the development of new therapeutic tools.

Funding Agency

FCT

Project Reference

–

Project Members

João Bessa

Principal Investigator Project Leader

Nuno Sousa

Principal Investigator

Rita Vieira

PhD Student

Main Project Outcomes

1. Reis, J.V.*, Vieira, R*., Portugal-Nunes, C., Coelho, A., Magalhães, R., Moreira, P., Ferreira, S., Picó-Pérez, M., Sousa, N., Dias, N., & Bessa, J. M. (2022). Suicidal ideation is associated with reduced functional connectivity and white matter integrity in drug-naïve patients with major depression. Frontiers in Psychiatry, 13(838111), 1-11. https://doi.org/10.3389/fpsyt.2022.838111 *Co-first Authorship.

2. Vieira R, Coelho A, Reis J, Portugal-Nunes C, Magalhães R, Ferreira S, Moreira PS, Sousa N and Bessa JM (2021) White Matter Microstructure Alterations Associated With Paroxetine Treatment Response in Major Depression. Front. Behav. Neurosci. 15:693109. https://doi.org/110.3389/fnbeh.2021.693109

3. Portugal-Nunes C, Reis J, Coelho A, Moreira PS, Castanho TC, Magalhães R, Marques P, Soares JM, Amorim L, Cunha PG, Santos NC, Costa P, Palha JA, Sousa N, Bessa JM. The Association of Metabolic Dysfunction and Mood Across Lifespan Interacts With the Default Mode Network Functional Connectivity. Front Aging Neurosci. 2021 Aug 2;13:618623. https://doi.org/110.3389/fnagi.2021.618623.

4. Morais, M.; Patrício, P.; Mateus-Pinheiro, A.; Alves, N.D.; MacHado-Santos, A.R.; Correia, J.S.; Pereira, J.; et al. "The modulation of adult neuroplasticity is involved in the mood- improving actions of atypical antipsychotics in an animal model of depression". Translational
Psychiatry 7 6 (2017). https://doi.org/1 10.1038/tp.2017.120

5. Morais, Monica; Santos, Paulo A. R.; Mateus-Pinheiro, Antonio; Patricio, Patricia; Pinto, Luisa; Sousa, Nuno; Pedroso, Pedro; et al. "The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition".
Journal of Psychopharmacology 28 12 (2014): 1178-1183. https://doi.org/110.1177/0269881114553646.

6. Bessa, J.M.; Morais, M.; Marques, F.; Pinto, L.; Palha, J.A.; Almeida, O.F.X.; Sousa, N.. "Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens.Translational Psychiatry 3 (2013) https://doi.org/110.1038/tp.2013.39

7. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, Almeida OF, Sousa N. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009 Aug;14(8):764-73, 739. https://doi.org/10.1038/mp.2008.119.

8. Prémio Artigo Destaque 2009 da Sociedade Portuguesa de Neurociências: Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, Almeida OFX, Sousa N (2009). The mood- improving actions of antidepressants do not depend on neurogenesis but are associated
with neuronal remodeling.

9. FCT Project PTDC/DTP-PIC/6936/2014 – Fundação para Ciência e Tecnologia (FCT). “A novel multimodal predictive approach of the effects of antidepressants in the recovery, remission and relapse of depression.“
10. Prémio Jovens Empreendedores 2013 da Associação Nacional de Jovens Empreendedores – Behavioural and Molecular Lab.