Cherise R Chin Fatt1, Crystal Cooper1, Manish K Jha2, Sina Aslan3, Bruce Grannemann1, Benji Kurian1, Tracy L Greer1, Maurizio Fava4, Myrna Weissman5, Patrick J McGrath5, Ramin V Parsey6, Amit Etkin7, Mary L Phillips8, Madhukar H Trivedi9. 1. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas; Advance MRI, LLC, Frisco, Texas. 4. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. 5. New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, New York. 6. Department of Psychiatry, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York. 7. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; Stanford Neurosciences Institute, Stanford University, Stanford, California; Sierra-Pacific Mental Illness Research, Education and Clinical Center, VA Palo Alto Healthcare System, Palo Alto, California. 8. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 9. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: madhukar.trivedi@utsouthwestern.edu.
Abstract
BACKGROUND: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. METHODS: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. RESULTS: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). CONCLUSIONS: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.
BACKGROUND: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. METHODS: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. RESULTS: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). CONCLUSIONS: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.
Authors: Nathan T M Huneke; Ibrahim H Aslan; Harry Fagan; Naomi Phillips; Rhea Tanna; Samuele Cortese; Matthew Garner; David S Baldwin Journal: Int J Neuropsychopharmacol Date: 2022-06-21 Impact factor: 5.678