The Pain of Depression

New brain imaging shows surprising findings linking depression and pain.

Posted Jul 31, 2019

Source: sheff/Shutterstock

Any person suffering from depression will tell you that they are in pain. Every day in my work as a psychiatrist I see patients in such agony. For some it is physical: An elderly Russian immigrant complains of a stabbing in his chest. A young Latina feels mysterious burning in her back. A dentist complains of constant roiling in his belly. For others, like a mother of two I recently saw, depression’s pain is a feeling of disconnection from others, a haunting alienation from all life’s pleasures.

As William Styron put in his classic book Darkness Visible: A Memoir of Madness, “The pain of severe depression is quite unimaginable to those who have not suffered it, and it kills in many instances because its anguish can no longer be borne. The prevention of many suicides will continue to be hindered until there is a general awareness of the nature of this pain.”

As a psychiatrist, this connection has long baffled me: Is it metaphorical or real?

Practitioners can theorize endlessly about such possibilities. Researchers, if fortunate, can collect data. Such was the case for our group at Columbia University’s Department of Psychiatry. Over the past several years, we completed two clinical trials of antidepressant medications combined with repeated MRI brain imaging for people with chronic depression. These studies compared antidepressants (the serotonin-norepinephrine reuptake inhibitors duloxetine in one study and desvenlafaxine in the other study) with placebo treatment over several months and obtained brain scans before and after treatment. Over the course of these two studies, we obtained more than 200 scans, and for the past several years we have been busy analyzing abnormalities related to the state of depression, and changes caused by treatment.

Our team began looking at measures of resting-state activity in the scans—that is, spontaneous activity of the brain when the patient lies in the MRI scanner, with her eyes shut, and lets her mind wander. The brain’s resting state is a fascinating one, because when the brain is 'at rest' there are characteristic patterns of activity. Analyzing the brain at rest reveals patterns of coordinated nerve cell activity—and these show how various brain centers are connected to one another. Resting-state MRI scans, therefore, can show ‘functional networks’ in the brain.

Suffice it to say, we were all surprised by the findings. The brain network that showed changes with antidepressant medicine—but not with placebo—involved the pain network. The pain network has been identified when studying people's responses to physical pain, and consists of a series  of connections from the cortex to lower-brain centers, the ‘thalamo-cortico-periaqueductal network.’ This network is central to processing pain, but it has never been previously connected to depression.

Antidepressant treatment with both medications (whether desvenlafaxine or duloxetine) decreased the activity of this network, suggesting that the alleviation of mental pain follows similar paths to what is seen with physical pain. In comparison, treatment with placebo had no effect on pain network activity. Not only that, but the more the symptoms of depression improved, the more the network’s activity decreased--suggesting that activity of those pathways is finely tuned to the severity of depression.

Our findings that antidepressant medications cause changes in the activity of the brain’s pain pathways appears to be part of how they relieve depression. To my thinking, this is important, since it is far from clear how antidepressants work within the brain.

Now that we have identified the pain network’s importance in depression treatment, a host of new questions arise. Would it be possible to design medicines to target these pathways, hopefully without being addictive? Or to use focused brain stimulation to alter these circuits’ activity? Beyond that, how might early life stresses, or trauma, or particular genes lead to the development of overactive circuits?

To me, both as a clinical psychiatrist and as a researcher, our findings only heighten the mysterious connections between pain and depression.

We already know that depression makes the pain worse and that people with medical conditions causing pain are more susceptible to developing clinical depression. People with ‘somatization disorder’ are cursed with both physical pain and mood disorders. But why? And why is mental pain experienced so differently from one person to the next, causing heartache for one, back pain for another? Why does one person sink into inactivity, whereas another is impelled toward danger, like PG Wodehouse’s character who searches for the leak in life’s gas-pipe with a lighted candle?

And how is the pain of depression connected to suicidal behavior? Suicide notes often contain the phrase, "I can't take the pain anymore!" When does the pain of depression become so intense that it compels desperate action? How can we—friends, family, and doctors—intervene before a person reaches that stage?

In the end, the findings of our two studies reinforce the value of listening deeply to our patients—and to our authors.

As author and philosopher C.S. Lewis put it, “Mental pain is less dramatic than physical pain, but it is more common and also more hard to bear."

This pain is real.


Wang Y, Bernanke J, Peterson BS, McGrath P, Stewart J, Chen Y, Wall M, Bastidas V, Hong S, Rutherford BR, Hellerstein DJ, Posner J. The association between antidepressant treatment and brain connectivity in two double-blind, placebo-controlled clinical trials. Lancet Psychiatry. 2019;

Sheline YI Yu M. Linking antidepressant performance with pain network connectivity. Lancet Psychiatry. 2019. 

Wager TD, Atlas LY, Lindquist MA, Roy M, Woo CW, Kross E. An fMRI-based neurological signature of physical pain. New England Journal of Medicine 2013;368:1388-97