PhD in Neuroscience

Contacts

Supervisor

Giuseppe Maina
Gianluca Rosso

Phd thesis

Treatment-resistant depression: neurocognitive correlates, peripheral biomarkers and integrated treatment strategies.

 

Abstract

Treatment-resistant depression (TRD) affects up to one third of patients with major depressive disorder and is loaded with functional impairments, mainly due to persistent cognitive disfunction. The picture of TRD still appears conflicting, especially regarding neurocognitive correlates and putative biological staging markers. A new spray medication approved for treatment of TRD is about to be commercialized, leading to unexplored new models of integrated treatments in real-world setting. The aims of this research project are to: 1) explore cognitive changes in TRD in comparison with non-resistant major depression; 2) identify markers to overcome current TRD staging models based on previous failed treatments; 3) evaluate in real-world TRD inpatients the efficacy of the new antidepressant treatment on depressive symptoms, cognitive profiles and global functioning, combined with a concurrent psychosocial treatment. With this research project we expect to contribute to deepen the knowledge on clinical, cognitive and biological aspects of TRD patients.

 

Background  

Depressive disorders are one of the major public health burdens (Ferrari et al, 2013), mainly due to the high numbers of individuals who have not exhibited a recovery from illness.
Despite the wide range of pharmacological and psychosocial treatments, only 50% of patients respond adequately to first line treatments (Rush et al, 2006; Kemp et al, 2008) and up to 30% of patients fail to achieve remission even with multiple lines of therapy (Rush et al, 2006; McLachlan et al, 2018) with great occupational and psychosocial impairments, mainly due to persistent cognitive disfunction related to depressive symptomatology (Lagerveld et al., 2010; McIntyre et al., 2014; Gill et al, 2021).  Treatment-resistant depression (TRD) is a complex and debilitating condition with heavily impacting consequences on healthcare and socio-economic system (Berlim et al, 2008); compared to those who do not develop treatment resistance, patients with TRD have a more severe and chronic course of illness. They are more likely to experience comorbid physical and psychiatric problems, to suffer from a significant functional impairment, and are more likely to attempt suicide (Vergunst et al., 2013).
Several staging models to classify TRD have been proposed, such as the Antidepressant Treatment History Form, the Thase and Rush Model, the European Staging Model, the Massachusetts General Hospital Staging Model, and the Maudsley Staging Model (Ruhé et al., 2012: McIntyre et al., 2014), but they are all based on previous failed treatments and not on a symptomatology profile (e.g. specific cognitive domains or severity of cognitive deficits) or biological markers. Thus, there is a growing interest in finding peripheral biomarkers related to TRD to allow an early detection of non-responder patients. A mixed panel including neurotrophic factors, pro-inflammatory cytokines and stress response mediators (plasma c-reactive protein (CRP)  interleukine 6 I(L6),  serum-interleukine 6 receptor (sIL6R), Tumor Necrosis Factor-a (TNF-a), Brain derived neurotrophic factors (BDNF), serum cortisol and the salivary Cortisol Awakening Response) has been studied, but data are still limited and conflicting (Yamasaki et al, 2019; Galvão et al, 2021). Our research group, in collaboration with the Neuroscience Institute Cavalieri Ottolenghi (NICO - Prof. Tempia’s research group) is running a translational study focused on the involvement of the enzyme glycogen synthase kinase-3 (GSK-3) in the pathogenesis of  mood disorders and preliminary results have shown how GSK-3b isoform seems to be differently expressed in major depressive disorder patients, pointing it as putative biomarker for the early detection of those patients (Poster presented at XXIII National Congress of Italian Society of Neuropsicopharmacology, 26-28/01/2022).
As of today, at the best of our knowledge, there are no recommended biomarkers to predict the risk of TRD or to guide treatment choice in TRD patients.
The management of TRD can be complex and difficult. It involves the use of multiple strategies such as augmentation therapies using second-generation antipsychotics, lithium, and triiodothyronine; switching to a different antidepressant class; combining therapies with different antidepressants; electroconvulsive therapy (ECT); and psychotherapeutic approach (Sapkota et al, 2021).
A possible breakthrough for the treatment of those patients in clinical practice can derive from antidepressants such as esketamine, with a novel mechanism of action based on stimulation of glutamate system and quick increases of neurotrophic factors release.

 

Research questions

The central aims of this research project are to:

• explore cognitive deficit and changes in TRD in comparison with non-resistant major depression;
• identify and study markers of illness predisposition and progression, exploring progressive clinical, biochemical and metabolic changes in the disease process, to overcome the current TRD staging models based on previous failed treatments;
• evaluate in acute real-world inpatients with TRD the efficacy of new antidepressant treatments on depressive symptoms, cognitive profile and global functioning, combined with a concurrent psychosocial treatment.

Research activities

Pubblications

Predicting outcome with Intranasal Esketamine treatment: a machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING).
Pettorruso M, Guidotti R, d'Andrea G, De Risio L, D'Andrea A, Chiappini S, Carullo R, Barlati S, Zanardi R, Rosso G, De Filippis S, Di Nicola M, Andriola I, Marcatili M, Nicolò G, Martiadis V, Bassetti R, Nucifora D, De Fazio P, Rosenblat JD, Clerici M, Dell'Osso BM, Vita A, Marzetti L, Sensi S, Di Lorenzo G, McIntyre R, Martinotti G and the REAL-ESK Study Group. Psychiatry Research. 2023. In press. https://doi.org/10.1016/j.psychres.2023.115378.

Assessing Adult ADHD Through Objective Neuropsychological Measures : a Critical Overview.
Rosso G, Portaluppi C, Teobaldi E, Di Salvo G, Maina G. J Atten Disord. 2023 May;27(7):786-794. doi: 10.1177/10870547231167564. Epub 2023 Apr 11. 

A Psychoanalytic-Derived Brief Psychotherapeutic Approach in the Treatment of Major Depression: Monotherapy Studies. 
Di Salvo G, Bianco M, Teobaldi E, Maina G, Rosso G. Medicina (Kaunas). 2022 Sep 23;58(10):1335.

Manic-Depressive Cycles in Bipolar Disorder: Clinical and Treatment Implications. 
Teobaldi E, Albert U, Di Salvo G, Mencacci C, Rosso G, Salvi V, Maina G. Psychopathology. 2021;54(2):98-105.

Aripiprazole Augmentation to Mood Stabilizers for Obsessive Compulsive Symptoms in Bipolar Disorder.
Di Salvo G, Maina G, Pessina E, Teobaldi E, Barbaro F, Martini A, Albert U, Rosso G. Medicina (Kaunas). 2020 Dec 24;57(1):9.

Inhaled Loxapine as an Option for Psychomotor Agitation in Complex Patients. Rosso G, Teobaldi E, Maina G. J Clin Psychopharmacol. 2020 Nov/Dec;40(6):645-647.

Did COVID-19 early lockdown actually lead to a higher rate of relapses in psychiatric patients?Rosso G, Teobaldi E, Maina G. Psychiatry Res. 2020 Sep;291:113204.

Book Chapters

Cotributor in Elementi di Psichiatria. IV Edition.
Maina G, Albert A, Rosso G – Edizione Minerva Medica. Published March 2023.

Disturbi d’ansia. Maina G, Rosso G, Teobaldi E. In Manuale di Psichiatria Rossi A, Amore A, Carpiniello B, Fagiolini F, Maina G, Vita A. - EDRA Edizioni S.p.A.
Published 30/09/2019

Research activities 

Participation as sub-investigator in:
- “Treatment-Resistant Depression Cohort in Europe TRD study – protocol 54135419DEP4001

- “Tipizzazione clinica del Disturbo Bipolare durata di malattia non trattata, caratteristiche di decorso e risposta ai trattamenti: uno studio retrospettivo” – protocol 71200206.

- “Cognitive rehabilitation in subjects with major depression treated with antidepressant: a multicentric randomized controlled pilot study”.

- “Ruolo di GSk-3 nei disturbi dell’umore” – protocol 10893206

- “A Non-interventional Cohort Study of Esketamine-Nasal Spray in Treatment-Resistant Depression – ECHO” – protocol 54135419TRD4008

- “Tipizzazione clinica del Disturbo Depressivo Maggiore. Predittori di resistenza, correlati neurocognitivi e risposta ai trattamenti: uno studio osservazionale.”

- “Strategie di trattamento della depressione maggiore resistente.”

International Congress abstract

“The role of GSK3 in mood disorders: preliminary data from an experimental study.”
G. Di Salvo, G. Rosso, E. Hoxha, E. Teobaldi, I. Balbo, F. Tempia, G. Maina. European Psychiatry. Special Issue S1. Volume 64. S382-S383.

Awards

3th classified in XXII Congresso Nazionale SOPSI 2018. Poster tytled ”Disturbo Bipolare e tipo di ciclo maniac depressive: studio clinic sperimentale su 806 pazienti”. Author F. Cuniberti, E. Teobaldi, U. Albert, G. Maina.

2nd classified in XXIV Congresso Nazionale SOPSI 2020. Poster tytled “Predittori di risposta ad aripiprazolo nel trattamento del DOC in comorbidità con disturbo bipolare”. Author: Pessina E, Martini A, Barbaro F, Teobaldi E, Di Salvo G, Rosso G, Maina G.

“Attilio Sabato” Award in XXIII Congresso Nazionale SINPF 2022. “Il ruolo di glicogeno sintasi chinasi 3 come marcatore di episodio depressivo maggiore in pazienti drugfree con disturbo bipolare o disturbo depressivo maggiore” Rizzo Pesci N, Di Salvo G, Porceddu G, Bianco M, Teobaldi E, Hoxha E, Balbo I, Tempia F, Maina G, Rosso G.

First award in memory of Prof. Nardini, XXIV Congresso Nazionale Società Italiana Psicopatologia, poster “Polarità prevalente e qualità della vita in pazienti con disturbo bipolare”. Teobaldi E, Bianco M, Porceddu G, Di Salvo G, Rosso G, Maina G.

2nd classified in XXVI Congresso Nazionale SOPSI 2022. Poster titled “L’attività di glicogeno sintasi chiansi 3 come marcatore nei disturbi dell’umore: risultati preliminari sui pazienti con distrbo bipolare o disturbo depressivo maggiore”. Rizzo Pesci N, Di Salvo G, Porceddu G, Bianco M, Teobaldi E, Hoxha E, Balbo I, Tempia F, Maina G, Rosso G.

2nd classidied in XXVII Congresso Nazionale SOPSI 2023. Poster titled “Fattori di rischio correlati a episodi affettivi nel peripartum in donne con disturbo bipolare”. Porceddu G, Teobaldi E, Maina G, Rosso G.

Teaching activities

Supplementary teaching activity. Course: Psychiatry. Bachelor's degree program: Educazione professionale - Savigliano campus. University of Turin

Subject expert to the teaching of “Psychiatry”. Faculty of Medicine and Surgery – San Luigi University Pole, University of Turin

 

Publications

All of my research products