The Antidepressant Advisor (Study 3): fMRI Study to Predict Treatment Response in Patients With Depression

NCT04342299 | Completed

• 4 other identifiers: ADeSS_S3PB-PG-0416-200392064430M816
• Study Type: observational
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

This prospective observational study (ADeSS-Study3) investigates candidate biomarkers prospectively predicting response to antidepressant medications and prognosis in major depressive disorder (MDD). Currently, about half of MDD patients will not respond to the first course of selective serotonin reuptake inhibitors (SSRIs), while more than 40% will also not achieve remission after a second round of another SSRI. There are functional magnetic resonance imaging (fMRI) measures in several brain regions, showing clinical potential as predictors of response and non-response to SSRIs. The overall aim of the study is to identify the neural signatures prospectively predicting poor prognosis in MDD patients after receiving four months of treatment in UK primary care. Specifically, it looks to evaluate four fMRI measures: 1) self-blame-selective subgenual cortex and ventral striatum connectivity with the right anterior temporal lobe; 2) pregenual anterior cingulate cortex activity in response to implicit emotional facial expressions; 3) amygdala activation in response to implicit emotional facial expressions; and 4) subgenual cingulate seed-based resting state. In addition, a more specific objective of the study is to provide the proof-of-concept for using fMRI to prospectively predict which MDD patients will not benefit from SSRI antidepressant treatments in UK primary care. The long-term translational aim is to identify such patients and provide them with alternative treatments without delay by informing a decision support system with the information provided by these candidate biomarkers. This study is linked to the Antidepressant Advisor Trial (ADeSS-Study 1: NCT03628027), in which the feasibility is evaluated of a novel computerised decision support system for antidepressant prescribing in MDD patients in a UK primary care setting.

Conditions

Major Depressive Disorder

Keywords

Major Depressive Disorder; Antidepressant Medication; Treatment Resistance; Biomarker Candidates; Functional Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (1)

• Baseline functional connectivity of the right superior anterior temporal lobe (RSATL) during self- vs. other-blame

  Functional connectivity will be measured using an optimised and shortened version of the so-called moral sentiment task. Statistical Parametric Mapping 12 (SPM12) will be used to determine psychophysiological interactions between previously reported RSATL seed and previously identified clusters of connectivity in BA25 and putamen/claustrum. These two connectivity measures will be compared for self-blame vs. other-blame and entered as two predictor variables into a logistic regression model. The logistic regression model will include responder/non-responder as a binary outcome variable. Response to treatment will be defined as a reduction of depressive symptom levels of at least 50%, as assessed by the self-rated QIDS-SR16 from baseline to last follow-up.

  4 months

Secondary Outcomes (3)

• Baseline functional connectivity of the subgenual cingulate cortex (SCC) during resting state fMRI

  4 months

• Baseline pregenual anterior cingulate cortex (pgACC) activity in response to implicit facial emotions

  4 months

• Baseline amygdala activation in response to implicit facial emotions

  4 months

Study Arms (2)

Responders

"Responders" are participants who show a reduction of depressive symptoms of at least 50%, as assessed by the self-rated Quick Inventory of Depressive Symptomatology (16-Item; self-report; QIDS-SR16) from baseline to follow-up. Please note that if the groups are skewed, a continuous measure (i.e. the difference between final and baseline depression scores) will be used rather than to categorise into responders and non-responders.

Non-responders

"Non-responders" are participants who do not show a reduction of depressive symptoms of at least 50%, as assessed by the self-rated Quick Inventory of Depressive Symptomatology (16-Item; self-report; QIDS-SR16) from baseline to follow-up. Please note that if the groups are skewed, a continuous measure (i.e. the difference between final and baseline depression scores) will be used rather than to categorise into responders and non-responders.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Most participants will be recruited through GP practices, based in South London, taking part in the Antidepressant Advisor Trial (Study 1: NCT03628027). In addition, other participants will be recruited through online advertising. While it is essential for the larger clinical trial to recruit participants directly linked to a GP practice (to allow for comparison), this is not a requirement for this study. Control participants (no personal or family history of MDD) are recruited by asking enrolled participants to ask their partner or friend whether they would be interested. Using this approach, control participants are likely to be from the same socio-economic and educational backgrounds to the participants.

You may qualify if:

• age 18 years +
• at least moderately severe major depressive syndrome on PHQ-9 (score 15 +)
• no plans to change GP practice
• able to complete self-report scales orally or in writing
• no previous prescription of mirtazapine or vortioxetine
• early treatment resistance as defined by 1) current or recent prescription (in the last 2 months) of any of the following antidepressants: citalopram, fluoxetine, sertraline, escitalopram, paroxetine, venlafaxine, or duloxetine AND 2) previous prescription of at least one other antidepressant out of the same list.

You may not qualify if:

• inability to consent to study
• unstable medical condition
• currently receiving specialist psychiatric treatment
• high suicide risk (MINI suicidality screen)
• past diagnosis of schizophrenia or schizo-affective disorder
• current psychotic symptoms (3 clinical screening questions)
• bipolar disorder
• currently at risk of being violent
• drug (modified PHQ) or alcohol abuse (PHQ) over last 6 months
• suspected central neurological condition
• pregnancy or insufficient contraception in women of childbearing age
• breastfeeding or within 6 months of giving birth in women of childbearing age
• both escitalopram and sertraline have already been prescribed
• MRI contraindications

Sponsors & Collaborators

• King's College London: lead
• NHS Lambeth Clinical Commissioning Group: collaborator

Study Sites (1)

King's College London, IoPPN

London, SE5 8AF, United Kingdom

Location

Related Publications (9)

• Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-88. doi: 10.2147/PPA.S29716. Epub 2012 May 1.

  PMID: 22654508 BACKGROUND

• Dunlop BW, Rajendra JK, Craighead WE, Kelley ME, McGrath CL, Choi KS, Kinkead B, Nemeroff CB, Mayberg HS. Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder. Am J Psychiatry. 2017 Jun 1;174(6):533-545. doi: 10.1176/appi.ajp.2016.16050518. Epub 2017 Mar 24.

  PMID: 28335622 BACKGROUND

• Godlewska BR, Browning M, Norbury R, Igoumenou A, Cowen PJ, Harmer CJ. Predicting Treatment Response in Depression: The Role of Anterior Cingulate Cortex. Int J Neuropsychopharmacol. 2018 Nov 1;21(11):988-996. doi: 10.1093/ijnp/pyy069.

  PMID: 30124867 BACKGROUND

• Williams LM, Korgaonkar MS, Song YC, Paton R, Eagles S, Goldstein-Piekarski A, Grieve SM, Harris AW, Usherwood T, Etkin A. Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial. Neuropsychopharmacology. 2015 Sep;40(10):2398-408. doi: 10.1038/npp.2015.89. Epub 2015 Mar 31.

  PMID: 25824424 BACKGROUND

• Lythe KE, Moll J, Gethin JA, Workman CI, Green S, Lambon Ralph MA, Deakin JF, Zahn R. Self-blame-Selective Hyperconnectivity Between Anterior Temporal and Subgenual Cortices and Prediction of Recurrent Depressive Episodes. JAMA Psychiatry. 2015 Nov;72(11):1119-26. doi: 10.1001/jamapsychiatry.2015.1813.

  PMID: 26445229 BACKGROUND

• Flandin G, Friston KJ. Analysis of family-wise error rates in statistical parametric mapping using random field theory. Hum Brain Mapp. 2019 May;40(7):2052-2054. doi: 10.1002/hbm.23839. Epub 2017 Nov 1.

  PMID: 29091338 BACKGROUND

• Thirion B, Pinel P, Meriaux S, Roche A, Dehaene S, Poline JB. Analysis of a large fMRI cohort: Statistical and methodological issues for group analyses. Neuroimage. 2007 Mar;35(1):105-20. doi: 10.1016/j.neuroimage.2006.11.054. Epub 2007 Jan 18.

  PMID: 17239619 BACKGROUND

• Fu CH, Steiner H, Costafreda SG. Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiol Dis. 2013 Apr;52:75-83. doi: 10.1016/j.nbd.2012.05.008. Epub 2012 Jun 1.

  PMID: 22659303 BACKGROUND

• Pessoa L, Adolphs R. Emotion processing and the amygdala: from a 'low road' to 'many roads' of evaluating biological significance. Nat Rev Neurosci. 2010 Nov;11(11):773-83. doi: 10.1038/nrn2920.

  PMID: 20959860 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Reader in the Neurocognitive Bases of Mood Disorders, Honorary Consultant Psychiatrist

Study Record Dates

• First Submitted: April 8, 2020
• First Posted: April 13, 2020
• Study Start: August 1, 2018
• Primary Completion: November 18, 2021
• Study Completion: November 18, 2021
• Last Updated: January 5, 2023

Record last verified: 2023-01

Locations

GB (1)