Treatment-resistant depression (TRD) is a growing problem in psychiatry. A recent meta-analysis has estimated TRD to be as high as 40%. Just over a decade ago, TRD was estimated to be as low as 10% to 15%. The causes of TRD are not fully understood. Finding ways to bring patients to remission faster may be part of the solution, but increasing our understanding of how depression works and how the brain responds to treatment may shed some light on this growing problem. Patients with TRD have been shown to have decreased volumes in gray matter structures, particularly in the hippocampus. Hippocampal volumes are correlated with decreased expression of neurotrophic factors (most notably, brain-derived neurotrophic factor [BDNF]), and decreased expression of BDNF correlates with the presence of depression. Increased expression of BDNF has a strong association with increased volumes in the hippocampus. Electroconvulsive therapy (ECT), a safe and effective treatment of severe depression, has been shown to be effective in TRD. Patients who undergo ECT have also had measurable increases in BDNF, indicating that ECT may be modulating intracellular processes in the patients with depression. Taken together, ECT may have a positive effect on restoring gray matter volume in patients with depression and especially TRD.