Short-term SSRI use alters brain connectivity in anxious individuals in unexpected ways

A study of anxious individuals found that 2-3 weeks of escitalopram administration altered the connectivity of their amygdala (a brain region involved in emotion processing and fear) with the dorsomedial cortex (a brain area involved in cognitive processing and regulating emotions) while viewing happy faces, compared to healthy individuals. However, the change was not in the expected direction. The paper was published in the Journal of Affective Disorders.

Anxiety disorders are a group of mental health conditions characterized by excessive fear, worry, or apprehension that is difficult to control and interferes with everyday functioning. They include conditions such as generalized anxiety disorder, panic disorder, social anxiety disorder, and several specific phobias. Although anxiety is a normal response to threat, in these disorders it becomes disproportionate, persistent, or triggered in situations that are not objectively dangerous.

Treatment typically includes psychotherapy, medication, or a combination of both. The medications most commonly used for long-term treatment are selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). These drugs increase the availability of the neurotransmitter (a chemical messenger in the brain) serotonin, or of serotonin and norepinephrine, in the brain and gradually modify neural systems involved in fear, mood, and stress regulation.

Study author Paulina B. Lukow and her colleagues note that connectivity between the amygdala and the dorsomedial cortex regions of the brain likely plays a key role in generating anxiety symptoms. A previous study found that connectivity between these two regions is increased in individuals suffering from anxiety while they are looking at (and cognitively processing) fearful faces, but not when processing happy faces.

The study authors hypothesized that increased serotonin availability in patients after SSRI administration would reverse these changes. In other words, they hypothesized that the connectivity between these two regions of the brain would be reduced after treatment with SSRIs. They conducted an experimental study.

Study participants were 45 individuals suffering from anxiety disorders and 96 healthy participants, included in the study as controls. Each of these two groups of participants was randomly further divided into two groups. In all groups, 74-86% of participants were women. Participants’ average age ranged between 23 and 28 years across groups. All participants were between 18 and 50 years of age.

One group of participants with anxiety was assigned to take one 10mg escitalopram tablet per day with or without food for 2-3 weeks, while the other group of participants with anxiety took an identical-looking tablet with no active ingredients (placebo) for the same period of time. The two groups of healthy participants received the same assignments. Participants did not know whether they were taking escitalopram or placebo. Escitalopram is an SSRI drug commonly used for treating depression and anxiety disorders.

Before the start of the treatment and after the treatment was finished, participants completed functional magnetic resonance imaging (fMRI, a scan that measures brain activity by detecting changes associated with blood flow) of their brains. While undergoing neuroimaging, participants completed an emotional faces task. In this task, they viewed alternating blocks of happy, fearful, and neutral faces. There were twelve blocks in total, four for each type of emotional face. Participants’ task was to label the gender of the faces shown by pressing a button. The point of this labeling was to make sure that participants were really looking at the faces shown and cognitively processing them while their brain activity was being recorded.

Unexpectedly, the results showed that anxiety symptoms did not improve for participants receiving escitalopram; instead, anxiety levels remained consistently higher in the anxious group compared to healthy controls regardless of the treatment they received. Furthermore, depression symptoms were higher across all participants (both with and without anxiety) who received escitalopram compared to those who received the placebo.

As the study authors expected, after escitalopram treatment, participants with anxiety disorders showed changes in the connectivity between the amygdala region and the dorsomedial cortex in both brain hemispheres compared to healthy controls. However, the change was in the opposite direction compared to what the study authors expected—the connectivity increased, while the study authors expected a decrease.

“These findings suggest that our simple hypothesis of SSRIs inducing a reduction in amygdala-dorsomedial cortex connectivity is incorrect, and the associated brain connectivity may instead increase in the initial weeks of drug administration,” the study authors concluded.

The study contributes to the scientific understanding of the neural underpinnings of anxiety disorders. However, the study authors note that their participants were recruited from the community rather than directly from mental health services, which may have resulted in the selection of participants with a different symptom profile compared to individuals who seek help for their mental health issues themselves.

The paper, “Brain activation and connectivity after 2–3 weeks of escitalopram administration in anxiety disorders: A randomised trial,” was authored by Paulina B. Lukow, Millie Lowther, Alexandra C. Pike, Yumeya Yamamori, Alice V. Chavanne, Siobhan Gormley, Jessica Aylward, Carlos Escalante Vera, Tayla McCloud, Talya Goble, Julia Rodriguez-Sanchez, Ella W. Tuominen, Sarah K. Buehler, Peter Kirk, and Oliver J. Robinson.