The hypothesis that antidepressants work by a “bottom-up” effect on the brain while cognitive therapies have a “top-down” effect has received support from imaging studies by researchers at the University of Toronto.

Senior author Helen Mayberg, MD, a Professor of Psychiatry and Neurology at Emory University in Atlanta, told NEUROPSYCHIATRY REVIEWS that response to cognitive behavior therapy is associated with a characteristic pattern of metabolic changes in the frontal cortex, cingulate, and hippocampus. These effects differ from changes in the prefrontal cortex, hippocampus, and subgenual cingulate seen with response to paroxetine, she observed.

“Depression is not just due to dysfunction in one of the nodes in this network. It also involves the failure of the remaining system to maintain homeostatic emotional control in times of increased cognitive or somatic stress,” Dr. Mayberg said. This failure may reflect genetic vulnerability, affective temperament, developmental insults, or environmental stressors. Recovery from depression is associated with modulation of specific targets within this greater depression network, many in regions that show no abnormalities at baseline. Treatments affecting different regions may be equally effective if the network as a whole retains enough compensatory capacity, she noted.

EFFECTIVE OPPOSITES

Working with Kimberly Goldapple, MSc, and associates at the University of Toronto, Dr. Mayberg showed that cognitive behavior therapy and paroxetine produce opposite changes in activity in the hippocampus and in the frontal cortex. In the hippocampus, cognitive behavior therapy increases activity while paroxetine decreases it; in the frontal cortex cognitive behavior therapy decreases activity while paroxetine increases it.

However, Dr. Mayberg said that these interesting differences may be less important than the fact that cognitive behavior therapy and paroxetine each affect unique regions that additionally have distinct connections to the areas commonly affected by both treatments.

The cognitive behavioral therapy study included 17 unmedicated, depressed patients (mean Hamilton Depression Rating Scale [HDRS] score, 20). Response criterion was at least a 50% decrease in HDRS. Fourteen of the 17 patients completed the cognitive behavioral therapy treatment course and showed a significant clinical response, including full remission in nine subjects. The other five patients had at least a 35% improvement in HRDS score.

In a previous randomized, double-blind, placebo-controlled trial of fluoxetine in depression, Dr. Mayberg had shown that clinical improvement occurred only in those patients who had decreases in limbic-paralimbic and striatal activity and increases in brainstem and dorsal cortex. Durable remission was associated with metabolic increases in prefrontal cortex and decreases in the subgenual cingulate and hippocampus.

USING THE BRAIN’S METABOLIC SIGNATURE TO GUIDE TREATMENT

Cognitive behavior therapy is thought of as a top-down approach because it focuses on using thinking functions to modulate abnormal mood states, modify attention and memory functions, change affective bias, and correct maladaptive information processing, Dr. Mayberg explained. Drug therapy is seen as a bottom-up approach because it first changes the chemistry in the brainstem, limbic, and subcortical sites system. It then produces secondary cortical changes with chronic treatment, altering more basic emotional and circadian behaviors and eventually causing “upstream” changes in depressive thinking.

Dr. Mayberg’s research focused on regions that are important in healthy emotional processes and abnormal in patients with depression. “We are interested in what happens in those areas in response to drug or other interventions,” she said. “We might have expected to find a common pathway. In fact, we found a final common system accessed in different ways by drugs and by cognitive behavior therapy.”

“Imaging has the potential for evidence-based decisions on one therapy versus another. It may also help us identify the patient who will be fine on cognitive behavior therapy without drug therapy from the one who needs the medication to benefit from cognitive behavior therapy,” Dr. Mayberg added. She also hopes that future imaging studies will help researchers learn why the placebo response rate in antidepressant drug trials is much higher today than in previous decades.

“The goal of this ongoing work is to identify markers that can be used to optimize treatment choices for the individual patient with depression. The metabolic signature of the pretreatment brain reflects both the underlying depression and the brain’s attempts at adaptation,” Dr. Mayberg said. “Patients who respond to cognitive behavior therapy differ at baseline from those who respond to paroxetine. If we can figure out the depressed patient’s ‘brain type,’ we might be able to deliver effective treatment for depression more promptly and to design better clinical trials. Imaging has the potential for providing evidence-based measures to predict which patient will do well without drugs and which will need medication to benefit from cognitive therapy,” she concluded.

—Janis Kelly

Suggested Reading
Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34-41.
Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193-207.
Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830-843.

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