State-Dependent Differences in Emotion Regulation Between Unmedicated Bipolar Disorder and Major Depressive Disorder

Rive et al use functional MRI to look at some of the differences between patients with bipolar depression and major depressive disorder.

Jessica Whelan, DNP, APRN, FPMHNP-BC

What do the results of this study mean for a practicing NP?

"The results of this study suggest to me that, when speaking with a patient presenting with a major depressive episode who could have either major depressive or bipolar disorder, I should consider a line of questioning regarding their emotional interactions throughout the lifespan, and their ability to regulate these emotions. These results suggest to me that emotional regulation could be a key differentiator between a depressive episode in MDD vs BPD.”

NP Psych Navigator contributors are paid consultants of AbbVie Inc. 

Symptoms in patients with major depressive disorder (MDD) and bipolar disorder may be difficult to distinguish clinically. This study provides important evidence that patients with MDD and bipolar disorder differ in their ability to regulate their emotions due to different neural mechanisms. Findings like this may aid in the development of new tools for improving diagnostic accuracy.

Why was the research needed?

MDD and bipolar disorder can have similar symptoms, particularly during the depressed and remitted phases. For example, previous research has suggested that both patient groups show impaired emotional regulation, which is the ability to control one’s emotional response to a stimulus or situation. While subjects with MDD and subjects with bipolar disorder both show decreased frontolimbic connectivity (ie, weak or abnormal communication between cortical regions in the frontal lobe and limbic structures in the temporal lobe), scientists think there may be different activity patterns mediating emotional regulation within the prefrontal cortex itself. Characterizing these potential differences may help with the development of additional diagnostic tools.  

What did the researchers do?

Four groups of patients were enrolled: patients in remission from MDD (n = 21) or bipolar disorder (n = 26), and patients experiencing a depressive episode due to MDD (n = 21) or bipolar disorder (n = 9). A healthy control group (n = 36), matching the patients for age and education, was also enrolled.

Researchers used functional magnetic resonance imaging (fMRI) to monitor brain activity while subjects completed a simple picture-based task. Subjects viewed 4 types of pictures (sad, happy, fearful, neutral) and were asked to either passively experience the emotion displayed before them (“attend” condition) or actively distance themselves from the emotion (“regulate” condition). After each picture, subjects were asked to rate the intensity of their emotions using a visual-analogue scale. These ratings were then used to derive an emotional regulation score (ie, how successful the subject was in regulating their emotions in the “regulate” condition versus the “attend” condition). For more information on how fMRI studies work, please see our Reader’s Quick Guide. 

What were the key results of the study?

Overall, the emotional regulation task was associated with expected patterns of brain activity in all subjects, including limbic regions for the “attend” condition and prefrontal regions for the “regulate” condition. Differences did emerge, however, when each patient group was examined individually.

Behavioral data indicated that the patients with remitted bipolar disorder showed poor emotional regulation, while the patients with remitted MDD performed similarly to the healthy controls. This effect was associated with increased brain activity in the dorsolateral prefrontal cortex (DLPFC; see our Reader’s Quick Guide) in patients with remitted bipolar disorder compared to patients with remitted MDD. The authors suggest the prefrontal hyperactivity in bipolar disorder may be compensatory in nature and reflect the patient’s otherwise impaired ability to regulate emotional responses.

The 2 groups of patients currently experiencing depressive episodes showed a different pattern of results, which varied by picture type (happy vs sad). Patients with bipolar depression showed normal performance on happy, but not sad, pictures, while patients with MDD showed equally poor performance for both categories. The authors suggest the results in bipolar disorder may reflect emotional conflict. While patients with bipolar depression could distance themselves from happy pictures because they were already feeling unhappy, distancing from sad pictures caused emotional conflict because they were feeling similar emotions. The emotional conflict related to sad pictures was also associated with increased activation of the rostral anterior cingulate cortex (rACC; see our Reader’s Quick Guide), which is thought to be involved in conflict monitoring and resolution.

Unlike bipolar disorder, there was no difference in rACC activity across happy and sad pictures in the MDD group. Currently depressed patients with MDD had difficulty regulating both happy and sad pictures and perceived both emotions as less extreme. According to the authors, this finding parallels the blunted emotional experience that is often cited as a symptom of MDD.

Group Task Performance
Main fMRI Finding


MDD, remitted

Increased DLPFC activity for all pictures in bipolar disorder vs MDD 
Bipolar disorder, remitted

Increased DLPFC activity for all pictures in bipolar disorder vs MDD
MDD, depressed

Increased rACC activity for sad pictures in bipolar disorder vs MDD
Bipolar disorder, depressed

Increased rACC activity for sad pictures in bipolar disorder vs MDD

✓ indicates normal emotional regulation (ie, performance did not differ significantly from healthy controls)
✕ indicates poor emotional regulation (ie, performance was significantly worse than healthy controls)
DLPFC, dorsolateral prefrontal cortex; fMRI, functional magnetic resonance imaging; MDD, major depressive disorder; rACC, rostral anterior cingulate cortex.

Why are these results important?

These results demonstrated that patients with MDD and patients with bipolar disorder perform differently on an emotional regulation task. These differences in emotional regulation were also “mood state-dependent”—that is, they differed between patients who were depressed and patients who are in remission. The researchers suggested that these qualitative differences in behavior reflect different pathophysiological mechanisms and may be useful in classifying individual patients with MDD or bipolar disorder.

Neuroimaging data also supported that qualitative differences exist between MDD and bipolar disorder. Accordingly, the researchers suggested developing a hierarchical diagnostic pipeline for mood disorders, combining standard clinical criteria (ie, DSM-5) with the results of behavioral and neuroimaging studies like this one.

Several limitations should be considered when interpreting these results. The primary limitation was the small number of patients with bipolar disorder (n = 9) currently experiencing depression, which limited statistical power and generalizability. All patients included in the study were also medication-free at the time of the testing, which is not representative of patients with MDD or bipolar disorder who rely on medication to manage and control symptoms. The results described here were also inconsistent with some previous research, including studies reporting decreased DLPFC activity in remitted patients with bipolar disorder. The authors suggested that these discrepant findings were likely due to differences in experimental design and task instructions; while patients in the current study were encouraged to use distancing as a means of emotional regulation, other studies have encouraged patients to use situation-focused reappraisal strategies. During reappraisal, subjects engage in more complex cognitive processes and try to reframe the situation so it becomes more neutral.

What’s next?

This study indicated that different neural mechanisms may account for emotional regulation in patients with bipolar disorder and patients with MDD. Additional research is needed to better characterize these differences, particularly in medication-naïve patients with different levels of depression severity. Future studies should also assess the diagnostic utility of these findings in clinical settings.

Reader’s Quick Guide

What is functional magnetic resonance imaging?

Functional magnetic resonance imaging, or fMRI for short, is a noninvasive technique used for measuring brain activity.2 During an fMRI experiment, a subject lies as still as possible in the scanner while they alternate doing two different cognitive tasks.2,3 For example, if the goal of the experiment is to study visual processing, the subject might be asked to switch between looking at shapes and closing their eyes.2,3 Scientists can then analyze the data to determine which areas of the brain show a pattern of activity that matches the task of interest.2 In other words, regions that show increased activity when the subject is looking at shapes relative to when the subject is closing their eyes will be interpreted as regions of the brain involved in visual processing.2,3

So, how does fMRI work exactly? The answer is complex, and scientists still have much to learn.2 But the short answer is that when a brain region becomes active, it consumes more oxygen.2 This causes more blood to flow to the region and replenish the oxygen.2 These changes in blood flow are the basis of fMRI and what is called the “blood oxygen level dependent” (BOLD) signal.2,3 

Neuroanatomy 101: A brief review of the terms discussed in this article

Anterior cingulate cortex (ACC): The front-most portion of the cingulate gyrus that curves around the genu of the corpus callosum; broadly involved in action-outcome learning, error detection, and conflict resolution, especially in the context of emotional processing.4-7

Dorsolateral prefrontal cortex (DLPFC): The portion of prefrontal cortex on the outer, lateral surface of the brain and above the ventrolateral prefrontal cortex; typically associated with working memory and cognitive control, as well as planning, strategy, and decision making.8-12

Limbic system: A group of cortical and subcortical brain structures that includes the amygdala, hippocampal formation, thalamus, hypothalamus, basal ganglia, and cingulate gyrus; has extensive connections with the body’s endocrine and autonomic nervous systems and helps to mediate emotion, motivation, and learning and memory.13-15


  1. Rive MM, et al. JAMA Psychiatry. 2015;72(7):687-96.
  2. UC San Diego Center for Functional MRI. What is fMRI? 2020. Accessed June 29, 2020
  3. Fox MD & Raichle ME. Nat Rev Neurosci. 2007;8(9):700-11. 
  4. Rolls ET. Brain Struct Funct. 2019;224:3001-3018. 
  5. Stevens FL, et al. J Neuropsychiatry Clin Neurosci. 23(2):121-5. 
  6. Kolling N, et al. Curr Opin Neurobiol. 2016;37:36-43. 
  7. van Veen V & Carter CS. Physiol Behav. 2002;77(4-5):477-82. 
  8. Badre D. Trends Cogn Sci. 2008;12(5):193-200. 
  9. Barbey AK, et al. Cortex. 2013;49(5):1195-205. 
  10. Petrides M. Philos Trans R Soc Lond B Biol Sci. 2005;360(1456):781-95. 
  1. Tsujimoto S, et al. J Neurosci. 2011;31(12):4583-92. 
  2.  Fuster JM. Neuron. 2001;30(2):319-33. 
  3. Karolinska Institute Central Nervous System- Visual Perspectives. Atlas. 2020. Accessed June 29, 2020. 
  4. Rajmohan V, Mohands E. Indian J Psychiatry. 2007;49(2):132-9. 
  5. Sokolowski K, Corbin JC. Front Mol Neurosci. 2012;5:55. 

ABBV-US-00434-MC, V2.0
Approved 01/2024
AbbVie Medical Affairs

This summary was prepared independently of the study’s authors.

This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient. 

Welcome To NP Psych Navigator

This website is intended for healthcare professionals inside the United States.
Please confirm that you are a healthcare professional inside the US.

No, I am not US Healthcare professional

You are now leaving NP Psych Navigator

Links to sites outside of NP Psych Navigator are provided as a resource to the viewer. AbbVie Inc accepts no responsibility for the content of non-AbbVie linked sites.

Redirect to:

Please to bookmark content