Patients with mood and anxiety disorders have have abnormally low activation in brain’s control circuit


New research published today in JAMA Psychiatry shows for the first time that patients with mood and anxiety disorders share the same abnormalities in regions of the brain involved in emotional and cognitive control.

The findings hold promise for the development of new treatments targeting these regions of the brain in patients with major depressive disorder, bipolar disorder, posttraumatic stress disorder, and anxiety disorders.

“These brain imaging findings provide a science-based explanation as to why patients with mood and anxiety disorders seem to be ‘locked in’ to negative mood states,” said Dr. Sophia Frangou, the study’s senior author and a psychiatry professor at UBC.

“They also corroborate the patients’ experience of being unable to stop and switch away from negative thoughts and feelings.”

Mood and anxiety disorders account for nearly 65 percent of psychosocial disability worldwide and represent a major public health challenge.

In Canada, one in three — or approximately 9.1 million people — will be affected by mental illness during their lifetime, according to Statistics Canada.

The defining symptoms of these disorders are persistent or recurring negative feelings, mainly depression and anxiety.

Frangou, who recently joined UBC as the President’s Excellence Chair in Brain Health at UBC’s Djavad Mowafaghian Centre for Brain Health, started this research as head of the research team at the Icahn School of Medicine at Mount Sinai, New York.

For the study, Frangou and her research team analyzed more than 9,000 brain scans from previous published studies that compared the brain activity of healthy adults to those diagnosed with a mood or anxiety disorder, ranging from major depression to post-traumatic stress disorder.

They found that patients exhibited abnormally low activity in the inferior prefrontal and parietal cortex, the insula and the putamen–regions that are key parts of the brain circuit for emotional and cognitive control and are responsible for stopping ongoing mental activities and switching to new ones.

They also discovered hyperactivity in the anterior cingulate cortex, the left amygdala and the thalamus, which work together to process emotional thoughts and feelings.

The findings hold promise for the development of new treatments targeting these regions of the brain in patients with major depressive disorder, bipolar disorder, posttraumatic stress disorder, and anxiety disorders.

Following her move to UBC, Frangou plans to pursue further research to leverage these findings toward more targeted interventions, such as non-invasive simulation of specific regions of the brain, that could improve outcomes for those living with mood and anxiety disorders.

The study is believed to be the largest analysis of brain scans of patients with mood and anxiety disorders to date. It was funded by the National Institute of Mental Health in the U.S., German research funding organization Deutsche Forschungsgemeinschaft, and the European Union’s Horizon 2020 Research and Innovation Programme.

Anxiety disorders are the most prevalent comorbid diagnoses in patients with bipolar disorder (BD). The lifetime prevalence of anxiety disorders is 45% when BD is present; patients with BD are 3 to 7 times more likely to meet criteria for diagnosis of an anxiety disorder than the general population.1,2 

Panic, posttraumatic stress (PTSD), and generalized anxiety disorders (GAD) are the most common (13% to 60%), followed by obsessive compulsive disorder (OCD; 10%).13 

Anxiety disorders and compulsive disorders, specifically OCD, will be addressed as a group because of the similar approaches used in treatment outside of the context of BD. For the purposes of this review, the terms anxiety and/or anxiety symptoms can be interpreted to also include obsessive and compulsive symptoms.

Comorbid anxiety symptoms have a significant impact on the treatment of BD leading to increased severity of bipolar symptoms and use of mental health services, more frequent and severe depressive episodes, non-adherence to treatment, and decreased functioning and quality of life (Table 1).46


Risk factors and impact of comorbid anxiety disorders and bipolar disorder4,5

Risk factors for comorbid anxiety disorders and bipolar disorder
 Earlier age of onset of bipolar disorder (early symptoms of anxiety in high-risk youth)
 Family history of mood disorders
 Female gender
 Childhood sexual abuse
 Adult sexual assault
 Comorbid personality disorder
Impact of comorbid anxiety disorders and bipolar disorder
 ↑ # mood episodes
 ↑ rate of depression as first episode
 ↑ rate of mixed episodes
 ↑ rate of rapid cycling
 ↑ frequency/severity of mood episodes
 ↑ periods of untreated illness
 ↑ time to remission
 ↑ suicidality
 ↑ risk of substance use
 ↑ severity of medication adverse events
 ↑ health care use
 ↑ psychological distress
 ↓ response to treatment
 ↓ adherence to treatment
 ↓ functioning and quality of life

Take Home Points

  1. Bipolar disorder (BD) with comorbid anxiety disorders is very prevalent and can lead to a higher illness burden, greater risk of residual symptoms upon resolution of the mood episode, and decreased medication adherence.
  2. There are limited clinical trials to provide evidence for medication and other treatments for comorbid BD and anxiety disorders. Mood stabilization is generally the first priority before addressing the anxiety disorder.
  3. Polypharmacy is the rule in the treatment of comorbid bipolar and anxiety disorders. Mood stabilizer monotherapy is unlikely to be effective for all symptoms. Recognition of the need for effective treatment of the anxiety disorder is paramount in improving quality of life and minimizing suicidality.
  4. Although serotonergic antidepressants, specifically selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, are first-line medication treatments for anxiety disorders, the use of antidepressants in BD may lead to destabilization of mood and a risk of manic switch, especially when used for long-term treatment. Serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants have been associated with a greater risk of manic switch than selective serotonin reuptake inhibitors and bupropion. Mood stabilizers and second-generation antipsychotics should be used as initial treatment before treatment with antidepressants. Lithium may be more protective against manic switch than other mood stabilizers. If antidepressant therapy is warranted, it should be undertaken with caution and close monitoring.

The goals of treatment for patients with comorbid anxiety and BD are remission of symptoms and a return to baseline functioning.

Anxiety commonly occurs during a depressive episode, which partly reflects the prevalence of the comorbid diagnoses of anxiety and mood disorders but does not explain anxiety symptoms occurring during euthymia.4 

Anxiety symptoms may not commonly remit with resolution of the mood episode; this leads to a progressive decrease in functioning and quality of life, even in euthymia. Residual anxiety symptoms may be a risk factor for limited success in the treatment of mood symptoms and may be predictive of mood symptom relapse.

In a recent study evaluating the effectiveness of venlafaxine versus lithium monotherapy in acute (n = 129, duration 12 weeks) and continuation (n = 55, duration 6 months) treatment of BD II depression, the investigators evaluated the impact of comorbid anxiety symptoms on depression relapse. Venlafaxine was more effective than lithium on depressive symptoms (P < .0001), but was less likely to improve symptoms of anxiety (P < .027). The rate of manic switch was not reported in this study.

Residual anxiety symptoms, especially uncontrollable worry, were a stronger predictor of depression relapse than residual depressive symptoms. The investigators concluded that remission of anxiety symptoms in bipolar depression may be protective against depressive relapse.7

The recognition and treatment of comorbid anxiety and BD remains an understudied area. Most published literature is descriptive in nature; few clinical trials exist related to pharmacologic and behavioral treatments.8 

University of British Columbia
Media Contacts:
Thandi Fletcher – University of British Columbia
Image Source:
The image is in the public domain.

Original Research: Open access
“Shared Neural Phenotypes for Mood and Anxiety Disorders: A Meta-analysis of 226 Task-Related Functional Imaging Studies”. Sophia Frangou et al.
JAMA Psychiatry doi:10.1001/jamapsychiatry.2019.3351.


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.