Distinguishing Bipolar Disorder from Major Depression

Brain activity while anticipating a working-memory task could help.

Posted May 11, 2020

Diagnosing bipolar disorder can be difficult. While it is not hard to distinguish between its two characteristic phases—the high spirits of mania and the low spirits of depression—it is challenging to tell if someone who reports low mood is suffering from a depressive disorder or is in the depressive phase of bipolar disorder. Indeed, a bipolar diagnosis is only confirmed, clinically, once a depressed patient has experienced at least one episode of mania.

Mania is characterized by elevated mood (either euphoric or irritable), racing thoughts, ideas and speech, ill-considered risk-taking, unusually high levels of energy, and a decreased need for sleep. Hypomania, a less intense version of mania, is no less serious and is also a feature of bipolar disorder’s manic phase. These symptoms are distinctly unlike those experienced during the depressive phase of bipolar disorder or by people suffering from a major depressive disorder. Yet symptoms of depression in themselves are clinically identical in people with depression and in the depressive phase of bipolar disorder.

This diagnostic problem has motivated researchers to search for measurable biological markers—aspects of brain activity, for example—that might differ in depressed patients and patients in the depressive phase of bipolar disorder, perhaps facilitating more accurate diagnosis. Preliminary success has now been reported in such an effort, led by Mary L. Phillips, Ph.D.

Phillips and colleagues at the University of Pittsburgh and the Western Psychiatric Institute and Clinic, including Holly A. Swartz, M.D., and first author Anna Manelis, Ph.D., followed clues from prior studies that pointed to potential differences in the way the brain prepares for and performs working-memory tasks in depressed individuals vs. those in the depressive phase of bipolar disorder.

Working memory is a system the brain uses to maintain, manipulate, and update information pertaining to tasks immediately at hand. Damage to neural networks that are engaged during working memory results in impairments in learning, reasoning, and decision-making that are observed in some people with mood disorders, including depression.

For their research, Phillips’ team recruited 18 people with bipolar disorder who were in the depressive phase of the illness; 23 with major depressive disorder who were also depressed; and 23 healthy controls. All of the participants received whole-brain scans with functional magnetic resonance imaging (fMRI), in two segments: one in which they were anticipating a task requiring working memory, and another in which they were actually performing the task. Each participant was scanned for both “easy” and “difficult” working memory tasks, and under conditions in which they were exposed to a range of emotional stimuli, from positive to neutral to negative.

These many permutations of working-memory tasks reflect the fact that people form expectations of what they need to do before performing a task, an assessment which can depend on whether the task is expected to be emotionally unchallenging or problematic. As the team suggests, subtle differences in the workings of brain circuits might be reflected when someone who heads into a task expects it to be difficult or stressful, as opposed to easy and pleasant.

Results of the analysis of the brain scans confirmed the hypothesis that patterns of brain activation during anticipation of a working-memory task vary according to whether the task is easy or difficult. Further, results suggested that anticipation and performance of working-memory tasks “can help distinguish depressed individuals with bipolar disorder from those with major depressive disorder.”

Specifically, patterns of activation in the lateral and medial portions of the brain’s prefrontal cortex during anticipation of easy vs. difficult tasks “may be an important biological marker for bipolar disorder vs. major depressive disorder classification,” the team wrote in a paper appearing in the journal Neuropsychopharmacology.

In trying to explain the measurable differences in neural activation they observed, the researchers theorized that “individuals with bipolar disorder may ‘block’ anticipation of negative stimuli to avoid negative emotions prior to performing a task.” They suggested such “blocking out” could be “a defensive mechanism that depressed individuals with bipolar disorder use to remain functional.”

Overall, they said their results bring “anticipatory processing into focus and suggests that anticipatory brain activation preceding performance on working memory tasks may be an important biological marker” of major depression and bipolar disorder, and suggest the possibility that targeting anticipatory processing could be a promising direction in developing future therapies for both conditions. They acknowledge that their results need to be replicated in larger cohorts, including in more people with a bipolar I diagnosis. Of the 18 bipolar patients in the current study, 80% were diagnosed with bipolar II.


Mary L. Phillips, Ph.D., a member of the BBRF Scientific Council, winner of the 2017 BBRF Colvin Prize for Outstanding Achievement in Mood Disorders Research and a 2005 BBRF Independent Investigator.

Holly A. Swartz, M.D., a 2006 BBRF Young Investigator.