UCLA

Approximately 40% of individuals seeking treatment for depression can be classified as having “treatment-resistant depression” (TRD), only 15% of whom will reach remission using a standard antidepressant. Electroconvulsive therapy (ECT) has lower drop-out and boasts remission rates over 60% within TRD. Despite this, little is known about the mechanisms of ECT’s clinical effects. Increased understanding of this may improve our ability to treat this highly prevalent, debilitating and intractable disease. Using longitudinal, multimodal data, the present studies explored neural and inflammatory mechanisms of ECT and its clinical efficacy. At pre-treatment (T1), <24 hours after their second ECT index (T2), and post-treatment (T3), TRD subjects (n=44) underwent magnetic resonance imaging, blood draws and clinical assessment. Clinical outcomes included post-treatment status as a Responder/Non-responder (≥50% reduction in global depression severity) and (exploratorily, in n=28) percent change in depressive symptom domains (affective, cognitive and vegetative). Study 1 examined ECT effects on volume/thickness in corticolimbic regions of interest (ROIs) in the brain, and their relationship with clinical outcomes. Following ECT, there were increases in the bilateral hippocampus, amygdala, striatum, anterior cingulate and insula, and left dorsolateral prefrontal cortex (DLPFC) and dorsomedial prefrontal cortex (DMPFC). These increases did not predict overall Response but did predict improvement in specific symptom domains. Larger DLPFC and DMPFC increases predicted greater improvement in affective symptoms; DLPFC increases also predicted cognitive symptom improvement. Study 2 assessed ECT effects on plasma inflammatory markers (CRP, IL-6 and TNF-α), and their changes in relation to clinical outcomes. Levels of CRP and IL-6 significantly increased at T2 relative to pre-treatment, and decreased from T2 to post-treatment. Neither early (%T2-T1) nor total (%T1-T3) changes in inflammation predicted clinical outcomes, however, post-treatment inflammation did moderate an association between early/acute inflammatory response and clinical outcomes. Larger early increases in IL-6 predicted greater reductions in both affective and cognitive symptom severity, in subjects with relatively higher post-treatment IL-6; though non-significant, the opposite relationship was seen in those with lower post-treatment IL-6. This same association was detected for CRP and reductions in neurovegetative symptoms. Finally, Study 3 assessed relationships between changes in inflammation and ROI volume/thickness, to test a mechanistic model of clinical response to ECT, in which increases in brain volume/thickness mediate the relationship between acute inflammatory response to ECT and clinical outcomes, conditioned by post-treatment inflammation levels. No evidence was found to support this hypothesis, however, as early inflammation changes were not associated with post-treatment changes in ROI volume/thickness. These findings support previous reports of ECT-induced increases in volume/thickness of brain regions putatively associated with depression, and that initial ECT administration is associated with a sharp increase in inflammation that decreases by end-of-treatment. These results also provide evidence of an association between such biological changes and clinical effects of ECT. Inconsistent literature on this topic may be at least partially due to frequent use of clinical outcomes that measure global, rather than symptom-specific, changes in symptoms. Additionally, these results indicate that, when examining peripheral mechanisms involved in ECT’s clinical effects, it may be important to consider the interaction between acute and long-term changes in such processes, rather than only the change between two data points. Lastly, no relationships were detected between changes in inflammation and changes in ROI volume/thickness. This may indicate that these processes exist independently, with distinct effects on clinical outcomes.