Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder

Abstract

Objective: The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions.

Method: Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes.

Results: The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT.

Conclusions: Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individual's probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

Trial registration: ClinicalTrials.gov NCT00360399.

Keywords: Antidepressants; Biological Markers; Brain Imaging Techniques; Cognitive Therapy.

Figure 1. Differential functional connectivity of subcallosal cingulate cortex between remitters and treatment failures with antidepressant medication or cognitive behavior therapy

A–C: Representative brain region and box plot of the z-score of the resting state functional connectivity with subcallosal cingulate cortex (SCC) between remitters (R) and treatment failures (TF) with each treatment type. The voxels identified by the subsample permutation testing (blue) are shown superimposed over voxels identified by the original ANOVA (yellow scale, see Methods). Box plots reflect contrasts using the permuted data. In all regions, the functional connectivity with the SCC seed is positive in CBT remitters and anti-correlated in CBT-treatment failures, whereas the inverse is true for antidepressant medication remitters and treatment failures. A, Dorsal midbrain, B, Ventrolateral prefrontal cortex BA 47/Insula (VLPF47/INS), C, Ventromedial prefrontal cortex BA10 (VMPF10). D: Box plots of the z-scores of the sum of the functional connectivity of the SCC with the three regions. The treatment by response interaction was significant at p=5e-10. CBT: Cognitive behavior therapy.

Figure 2. Correlation between percent change in depression severity and the summed functional connectivity of subcallosal cingulate cortex across all patients by treatment type

Correlation between summed functional connectivity and subjects’ percent change in HDRS score across all 122 patients with analyzable fMRIs. The left panel with blue symbols show the data for the medication-treated patients; the right panel with green symbols shows that for the CBT-treated patients. The correlations between Summed Functional Connectivity Scores and the percent HDRS change were significant for both treatments, though the strength of the correlation was stronger among CBT treated patients (r= −0.539, p<.001) than among medication-treated patients (r=0.258, p<.017). Summed functional connectivity reflects the added scores of the functional connectivity of the cingulate cortex resting state with each of the 3 regions identified in Figure 1. “Intermediate response” subjects had ≥30% improvement in HAMD-17 score, but did not meet criteria for remission. HDRS-17: 17-item Hamilton Depression Rating Scale

Figure 3. Receiver operating characteristic curves for classification of remission and treatment failure outcomes with CBT and medication treatment

ROC curves for A) remission, and B) treatment failure, showing optimal summed functional connectivity values for classifying these respective outcomes for each treatment. Blue color represents medication, green represents CBT.

Figure 4. Individual subjects’ summed functional connectivity scores grouped by treatment outcome

Strip charts demonstrating individual subjects’ summed functional connectivity scores. Green triangles represent CBT-treated patients; blue triangles represent medication-treated patients. A) Upward-pointing triangles represent remission; downward-pointing triangles represent non-remission. For maximizing remission outcomes, z-scores >0.18 indicate CBT should be selected; z-scores <0.10 indicate medication should be chosen. B) Upward-pointing triangles represent any level of response (partial response, response, or remission); downward-pointing triangles represent treatment failure. To minimize treatment failure, z-scores <−0.02 indicate CBT should be avoided; z-scores >0.11 indicate medication should be avoided.