1 Goldapple K.

Segal Z.

Garson C.

Lau M.

Bieling P.

Kennedy S.

Mayberg H. Modulation of cortical-limbic pathways in major depression: Treatment-specific effects of cognitive behavior therapy.

In 2004, Archives of General Psychiatry published a study by Goldapple et al. () that transformed the way we think about the treatment of depression. It is cited in textbooks of psychotherapy and psychopharmacology alike; inclusion of key figures from the article seems requisite to any PowerPoint presentation. The study went like this: a group of researchers led by Helen Mayberg were interested in comparing how the brain responded to different types of treatment. They recruited two groups of patients with depression. One group was treated with cognitive behavioral therapy (CBT); a separate group of patients (whose data had already been published) were treated with the antidepressant medication paroxetine. All patients received positron emission tomography scans before and after treatment. Both groups showed comparable improvements in their depression, and both groups showed changes in functional activation in the hippocampus and frontal cortex. What was surprising—and what made the paper impactful—was that the brain activation patterns in CBT and paroxetine were exact opposites of each other (patients who received paroxetine showed decreased hippocampal activation and increased prefrontal activation; patients who received CBT showed increased hippocampal and decreased prefrontal activation). How could it be that such different effects on the brain could both lead to improvements in depression? The authors hypothesized that the net change to the hippocampal–frontal cortex pathway was the same. The difference was that CBT, by targeting attention, cognition, and emotional processing, works by a “top-down” mechanism, whereas antidepressant drugs work from the “bottom-up,” targeting vegetative processes in more subcortical regions. This narrative—of dissociable top-down versus bottom-up processes—has become a dominant way of framing how treatment works, both within the research community and in how we communicate with patients.