Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder

Abstract

Context: The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods.

Objective: To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD.

Design: A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face-identity and face-emotion working memory tasks.

Setting: National Institute of Mental Health Division of Intramural Research Programs.

Participants: Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age.

Main outcome measure: The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygen level-dependent (BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups.

Results: Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline.

Conclusion: These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine.

Trial registration: clinicaltrials.gov Identifier: NCT00055575.

Conflict of interest statement

Conflict of Interest Disclosures: The National Institute of Mental Health has filed a use patent for the use of scopolamine in the treatment of depression, and Drs Furey and Drevets are identified as coinventors on this pending patent application in the United States and an existing patent in Europe. Dr Zarate is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government.

Figures

Figure 1

Experimental design.

Figure 2

Working memory task. Participants were presented with a 3-second picture of a face to encode, followed by a 15-second delay/maintenance period, followed by a presentation of a 3-second picture of a test face. Trials were separated by a 15-second intertrial interval (ITI). Subjects were instructed to attend to either the identity or the emotional expression of the face during the encoding period and to indicate a match or nonmatch during the test period based only on the attended feature. Images from the Karolinska Directed Emotional Faces stimulus set were used to create the task; the models in the Figure include F06, F15, and F31.

Figure 3

Areas of the bilateral middle occipital cortex that show correlations (voxel P <.005; whole-brain correlation P <.05) between treatment response to scopolamine and baseline blood oxygen level–dependent (BOLD) response to the encoding component of a working memory task when attending to emotion are shown. The representative scatterplots and the best-fit lines for the right (A) and left (B) hemispheres are presented. MADRS indicates Montgomery-Asberg Depression Rating Scale.

Figure 4

Areas of the bilateral middle occipital cortex that show correlations (voxel P<.005; whole-brain correlation P<.05) between treatment response to scopolamine and baseline blood oxygen level–dependent (BOLD) response to the test component of a working memory task when attending to emotion are shown. The representative scatterplots and best-fit lines for the right (A) and left (B) hemispheres are presented. MADRS indicates Montgomery-Asberg Depression Rating Scale.

Figure 5

The area of the left middle occipital cortex where the change in blood oxygen level–dependent (BOLD) response following scopolamine administration (drug –placebo) correlates (voxel P <.05; small volume correction P <.05) with subsequent treatment response as measured during the encoding (A) and test (B) components of a working memory task while attending to emotion. The representative scatterplots and best-fit lines are shown. MADRS indicates Montgomery-Asberg Depression Rating Scale.

Figure 6

Baseline blood oxygen level–dependent (BOLD) responses during the encoding (A) and test (B) components of a working memory task while attending to emotion are shown for healthy participants and patients with major depressive disorder (MDD) for the left and right middle occipital cortex. Regions were defined from correlation analyses. The error bars reflect standard error.

Figure 7

Mean reaction times when performing the emotion and identity working memory tasks are shown for patients as measured during placebo and scopolamine administration. The error bars reflect standard error of the mean.