Prediction of the Therapeutic Response in Depression Based on Neuro-computational Modeling Assessment of Motivation

Official title

Prediction of the Therapeutic Response in Depression Based on an Early Neuro-computational Modeling Assessment of Motivation

Overview

This study aims to better understand the mechanisms of action of antidepressants, but also the neural correlates of motivation deficits. One hundred patients with a moderate to severe major depressive episode will be enrolled in this prospective multicenter study. The objective will be to predict the therapeutic response to two first-line antidepressants on the basis of an early neurocomputational assessment of motivation. Antidepressant treatment will be administered as monotherapy after randomization between two drugs: escitalopram and vortioxetine. Patients will undergo six visits and follow-up for one year. The investigators will combine computer modeling and functional MRI to identify motivational deficits and elucidate their brain correlates before initiation, after 7 days and after 6 months of treatment. 36 healthy volunteers will also be included to allow comparison with patients with depression. They will not receive any treatment.

Detailed description

One hundred patients with a moderate to severe major depressive episode will be enrolled in this prospective multicenter study. Six visits will be scheduled within a year:

* V0 (inclusion visit): verification of inclusion and exclusion criteria, information, and consent. * V1 (before randomization - baseline state):

* Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. * Neuro-cognitive evaluation using a battery of tests to explore motivation, emotion processing, belief construction, and their updating. Part of the tests will be performed during the functional MRI session. * Structural (anatomical) and functional MRI, ASL. * Blood samples. * Randomization and introduction of the new antidepressant will occur immediately after V1. To maximize acceptability by referring psychiatrists, dosage and co-prescriptions will be at the discretion of the psychiatrist in charge, but the assigned treatment will not be changed for 4 weeks (until V3). * V2 (7 days after the beginning of the new antidepressant - 'early response visit'):

o Similar to V1. * V3 (28 days after the beginning of the new antidepressant - 'conventional response visit'):

* Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. * Blood samples * V4 (6 months after the beginning of the new antidepressant - 'remission visit'):

* Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction. * Cognitive evaluation using a battery of tests to explore motivation, emotion processing, belief construction, and their updating. * Structural (anatomical) MRI, ASL * Blood samples * V5 (one year after the beginning of the new antidepressant - 'functional remission visit'):

* Clinical evaluation using validated questionnaires for the severity of depression, quality of life, anhedonia, apathy, and cognitive dysfunction.

36 healthy volunteers without a history of neurologic or psychiatric disorder, matched for age, gender, and education will be included. They will perform V0-V2 (without MRI and blood sample at V2). Healthy volunteers will not receive any treatment as part of the research.

Interventions

• Other escitalopram
  Patients will receive an antidepressant strategy : escitalopram. The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist. After 4 weeks, the strategy can be adapted by the refeering psychiatrist exactly as if the patient had not been included in the trial.
• Other vortioxetine
  Patients will receive an antidepressant strategy : vortioxetine. The strategy will not be modified for a period of 4 weeks. Dosage adjustment and co-prescriptions will be at the discretion of the refeering psychiatrist. After 4 weeks, the treatment strategy can be adapted by the refeering psychiatrist exactly as if the patient had not been included in the trial.

Primary outcome measures

• Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the early changes (differences between V1 and V2) of the computational phenotype of depressed patients. [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant) and V3 (after 28 days of antidepressant)]

Secondary outcome measures (12)

• Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the early changes (differences between V1 and V2) of the neuro-computational phenotype of depressed patients [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant) and V3 (after 28 days of antidepressant)]
• Prediction of the therapeutic response (MADRS score) 28 days after the introduction of the antidepressant strategy (V3) based on the initial (baseline state- V1) neuro-computational phenotype of depressed patients [Time frame: Baseline state (before the start of antidepressant strategy), and V3 (after 28 days of antidepressant)]
• Prediction of long-term remission (V4) based on the early changes (differences between V1 and V2) of the neuro-computationnal phenotype of depressed patients [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant), V4 (6 months after the start of antidepressant)]
• Prediction functional remission (V5) based on the early changes (differences between V1 and V2) of the neuro-computationnal phenotype of depressed patients [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant), V5 (1 year after the start of antidepressant)]
• Prediction of relapse at one year (V5) based on the computationnal phenotype of remitted patients at 6 months (V4). [Time frame: V4 (6 months after the start of antidepressant), V5 (1 year after the start of antidepressant)]
• Description of the motivational deficit of depressed patients at baseline (V1). [Time frame: Baseline state (before the start of antidepressant strategy)]
• Description of the neural correlates of motivation deficits of depressed patients at baseline (V1). [Time frame: Baseline state (before the start of antidepressant strategy)]
• Description of the evolution of motivation deficit of depressed patients after one week of antidepressant treatment [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant)]
• Description of the evolution of the neural correlates of motivation deficits after one week of antidepressant treatment [Time frame: Baseline state (before the start of antidepressant strategy), V2 (after 7 days of antidepressant)]
• Description of the evolution of motivation deficit of depressed patients at 6 months [Time frame: Baseline state (before the start of antidepressant strategy), V4 (6 months after the start of antidepressant)]
• Description of the evolution of the structural neural correlates of depression after 6 months of treatment [Time frame: Baseline state (before the start of antidepressant strategy), V4 (6 months after the start of antidepressant)]
• Description of the evolution of the functional neural correlates of depression after 6 months of treatment [Time frame: Baseline state (before the start of antidepressant strategy) V4 (6 months after the start of antidepressant)]

Eligibility criteria

Patients with major depressive disorder

Inclusion criteria

• Meeting DSM-5 criteria for major depressive disorder (single or recurrent episodes)
• With a MADRS score >= 24
• For which a new line of treatment is needed
• No previous line of antidepressant for this episode or wash-out long-enough to avoid carry-over effects
• Valid health care insurance

Exclusion criteria

• Treatment-resistant depression (defined as insufficient response despite at least 2 trials of antidepressant prescribed at adequate dose and duration)
• Subjects with a trial of escitalopram and/or vortioxetine for the current episode, or with contra-indication to one of these two drugs
• Subjects with a diagnostic of persistent depressive disorder, bipolar disorder or schizophrenia, neurodeveloppemental disorder, unremitted substance abuse disorder other than tobacco, personality disorder severe enough to compromise the follow-up (based on investigator's appreciation).
• Subject with a history of neurological disorder: parkinson's disease, dementia
• Contraindications to MRI scanning: pregnancy, claustrophobia, metallic implants
• Pregnant or breastfeeding women
• involuntary hospitalisation and legal protection measures

Healthy volunteers

Inclusion criteria

\- Valid health care insurance

Exclusion criteria

• Subjects with a diagnostic of persistent depressive disorder, bipolar disorder or schizophrenia, neurodeveloppemental disorder, unremitted substance abuse disorder other than tobacco, personality disorder severe enough to compromise the follow-up (based on investigator's appreciation).
• Subject with a history of neurological disorder: parkinson's disease, dementia
• Contraindications to MRI scanning: pregnancy, claustrophobia, metallic implants
• Pregnant or breastfeeding women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 5 centers

• Groupe hospitalo-universitaire de Grenoble Alpes — La Tronche
• Centre hospitalier Universitaire de Lille — Lille
• Centre hospitalier Universitaire de Saint-Etienne — Saint-Priest-en-Jarez
• Groupe hospitalo-universitaire Assistance Publique, hôpital Pitié Salpêtrière - Hôpitaux d — Paris
• - Groupe hospitalo-universitaire Paris Psychiatrie et Neurosciences — Paris

Publications

• Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ; World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J B PMID 23879318
• Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, Parikh SV, Patten SB, Ravindran AV; Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009 Oct;117 Suppl 1:S26-43. doi: 10.1016/j.jad.2009.06.041 PMID 19674794
• Uher R, Perlis RH, Henigsberg N, Zobel A, Rietschel M, Mors O, Hauser J, Dernovsek MZ, Souery D, Bajs M, Maier W, Aitchison KJ, Farmer A, McGuffin P. Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med. 2012 May;42(5):967-80. doi: 10.1017/S0033291711001905. Epub 2011 Sep 20. PMID 21929846
• Pessiglione M, Vinckier F, Bouret S, Daunizeau J, Le Bouc R. Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases. Brain. 2018 Mar 1;141(3):629-650. doi: 10.1093/brain/awx278. PMID 29194534
• Clery-Melin ML, Schmidt L, Lafargue G, Baup N, Fossati P, Pessiglione M. Why don't you try harder? An investigation of effort production in major depression. PLoS One. 2011;6(8):e23178. doi: 10.1371/journal.pone.0023178. Epub 2011 Aug 10. PMID 21853083
• Mauras T, Masson M, Fossati P, Pessiglione M. Incentive Sensitivity as a Behavioral Marker of Clinical Remission From Major Depressive Episode. J Clin Psychiatry. 2016 Jun;77(6):e697-703. doi: 10.4088/JCP.15m09995. PMID 27337420
• Le Heron C, Plant O, Manohar S, Ang YS, Jackson M, Lennox G, Hu MT, Husain M. Distinct effects of apathy and dopamine on effort-based decision-making in Parkinson's disease. Brain. 2018 May 1;141(5):1455-1469. doi: 10.1093/brain/awy110. PMID 29672668
• Wardle MC, Treadway MT, Mayo LM, Zald DH, de Wit H. Amping up effort: effects of d-amphetamine on human effort-based decision-making. J Neurosci. 2011 Nov 16;31(46):16597-602. doi: 10.1523/JNEUROSCI.4387-11.2011. PMID 22090487

Identifiers

NCT: NCT05866575 · D20-P059

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗