Antidepressant Efficacy Is Linked to Functional Connectivity of Brain Regions Involved in Cognitive Control

Post by Shireen Parimoo

What's the science?

Major depressive disorder (MDD) includes symptoms like difficulty concentrating, changes in sleep and appetite, and reductions in cognitive control. Many medications for depression exist, but the treatment process is often complicated, due to the heterogeneity in patients’ responses. Moreover, different classes of antidepressant medications have different neurobiological effects on the brain. Depression is associated with altered neural connectivity, including between brain regions involved in cognitive control like the dorsolateral prefrontal cortex (DLPFC) and the supramarginal gyrus (SMG). This altered connectivity is related to performance on tasks where inhibiting a response is needed, or flexible, adaptable behavior is required. Past research suggests that the functional connectivity of cognitive control regions may be related to the efficacy of different medications. This week in Biological Psychiatry, Tozzi and colleagues used functional magnetic resonance imaging (fMRI) during a clinical trial to examine the relationship between functional connectivity and the efficacy of different classes of antidepressants.

How did they do it?

Participants included 124 patients diagnosed with MDD and 59 healthy controls matched on age and sex. Patients were randomly assigned to receive one of three antidepressants: sertraline, venlafaxine-extended release, or escitalopram. All participants performed a go/no-go task (see below) while undergoing fMRI scanning during both a baseline session and a post-treatment session 8 weeks later. Patients were additionally assessed on the severity of their depressive symptoms at two different time points to determine whether their symptoms improved following the treatment. Those who showed greater than 50% improvement in symptom severity were classified as “responders”, and those who didn’t were classified as “non-responders”.

In the go/no-go task, participants were instructed to respond to the word “PRESS” by pressing a button when the word was shown in a green font (“go” trials) but withhold their response when the font was red (“no-go” trials). A comparison of brain activity during no-go and go trials revealed greater activation in cognitive control regions like the right SMG, the left orbitofrontal cortex (OFC), and the right middle temporal gyrus (MTG). The authors used generalized psychophysiological interaction analysis to examine the functional connectivity between these regions. They compared the findings across the patient and control groups, within participants at the different time points, and between responders and non-responders within each treatment group.  

What did they find?

Task performance was similar in MDD patients and healthy controls, and across the three treatment groups. Sertraline responders had higher connectivity between the SMG and the MTG and between the DLPFC and the SMG on no-go trials at baseline compared to healthy controls, whereas venlafaxine responders had lower connectivity between these pairs of regions. Sertraline responders also had greater connectivity between the DLPFC-SMG and the SMG-MTG compared to non-responders and higher connectivity between the cerebellum and anterior insula compared to non-responders and healthy controls. The enhanced connectivity in sertraline responders was associated with greater symptom improvement following treatment. The opposite pattern was observed among venlafaxine responders, who had reduced connectivity between these regions, which was related to a larger improvement in symptom severity. Thus, patients with higher connectivity between cognitive control regions responded better to sertraline, whereas those with lower connectivity responded more to venlafaxine. Functional connectivity in the escitalopram group did not differ from healthy controls at baseline and was not associated with response outcome. 

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Functional connectivity at baseline was related to improvement in symptom severity in the sertraline and venlafaxine groups. Compared to baseline, sertraline responders showed a reduction in the connectivity between the left precentral gyrus and the left superior temporal gyrus at the post-treatment scan. In contrast, venlafaxine responders had increased connectivity between the left OFC and the brainstem, and between the left OFC and the left caudate nucleus. Importantly, functional connectivity changes among sertraline and venlafaxine responders were linked to symptom improvement and were only observed on no-go trials, suggesting that the antidepressants had a specific effect on the brain regions involved in response inhibition.

What's the impact?

This study is the first to show that individual differences in the connectivity of the cognitive control network during response inhibition are linked to the efficacy of different classes of antidepressant medications. These findings have important implications for how clinicians might prescribe antidepressants in the future and open the door for exciting new research on the development of targeted treatment plans for MDD patients.


Tozzi et al. Connectivity of the cognitive control network during response inhibition as a predictive and response biomarker in major depression: evidence from a randomized clinical trial. Biological Psychiatry (2019). Access the original scientific publication here.