Note to the Reader: The following article discusses material of a potentially upsetting nature. While the narrative details are fictional, the ideas and themes—both scientific and personal—are real. Information regarding resources for those in crisis can be found at the end of this article.

by Emily Orwell
figures by Sean Wilson

I’m having one of those days. You know, the type where I accidentally slice my finger open while chopping vegetables.

Even as I rinse and band-aid my finger, my body and brain are working together to create the feeling of pain. My nervous system is made up of neurons that “talk” to each other primarily though chemicals called neurotransmitters, or alternatively, through electrical signals (Figure 1). Specialized neurons in my skin detect the damage and send “warning signals” which travel through my spinal cord, to more neurons, and finally to the brain. The processing of pain in the brain is complex, and multiple regions are involved in forming the sensation of a knife cut. This kind of acute pain is unpleasant, but it’s an evolutionary necessity: pain sends important signals to warn against dangerous or harmful situations.

Eventually, dinner is ready, so I grab my meal and start a movie on Netflix. Film, like so many other art forms, can elicit emotions of happiness and exhilaration—or, less pleasantly, fear, anger, and sadness. Processing of emotions, positive or negative, has long been attributed to the brain’s limbic system, which is nestled in the inner part of our brain and consists of at least a dozen smaller structures. Incidentally, the limbic system also enables us to sense and react to our environment through pain. Like physical pain, emotions have evolutionary importance. For instance, fear helps us avoid danger. More generally, emotions are powerful motivators of our actions and reinforce behaviors that help maintain an orderly society.

At the most basic level, pain and emotions come from the same neuron-messaging system. For this to happen properly, the close to 100 billion neurons in my body are organized into intricate neural circuits (Figure 1). Neurons rarely, if ever, work in isolation: a single neuron can physically connect to and receive incoming signals from up to 10,000 neurons while also sending outgoing signals to another 10,000 neurons.

Considering the staggering number of neurons involved, our neural circuitry works remarkably well nearly all the time. And when it works the way it’s supposed to, pain or sadness eventually go away.

Chronic pain and depression: consequences of a nervous system gone awry

The immediate acute pain from my cut is a direct consequence of my injury. If my nervous system is on the right track, the pain should recede once the injury heals. But this time around, something goes wrong. My nervous system gets derailed, and months after my knife wound has completely healed, I still experience a frustrating mystery pain in my hand.

This makes me one of an estimated 25.3 million American adults who experience chronic pain (Figure 2). This means that close to 1 in 10 of your friends and colleagues is affected. For some sufferers, the pain is easily attributed to an injury or an illness, but for others, the reasons for the pain are unclear. In my case, the cause is obviously the knife wound, but the persistence is mystifying. A more severe version of this phenomenon is unfortunately common among amputees: it’s estimated that 40-80% of amputees experience serious phantom limb pain in the body part that has been removed. In such cases, chronic pain does not stem from obvious physical damage but reflects a nervous system that cannot “turn off” the pain signal.

At the same time as I’m experiencing pain, I find another similarly constant and unwanted companion: chronic depression. Depression is a complicated illness, and no two sufferers experience the same thing. It is commonly likened to sadness but can encompass other feelings, such as emptiness and lethargy. When I experience normal sadness, I can identify a specific cause, and I know that I will feel better eventually. Depression is different. It can start suddenly and, unlike normal emotions, can linger indefinitely (Figure 2).

Measuring the comorbidity, or simultaneous co-occurrence, of pain and depression is challenging, so there are no definitive numbers on how many suffer from both conditions. Nevertheless, studies generally agree that compared to the general populace, people who suffer from one are more likely to have the other. Some suggest that 30-50% of Americans experiencing chronic pain will also experience depression, while other estimates go as high as 85%. Similarly, it’s estimated that, on average, 65% of those suffering from depression also experience pain. Regardless of the exact numbers, there are undoubtedly millions who go to bed every night hurting in body and mind, and who wake up to the same every day.

Two rotten apples from the same tree

Why did I get unlucky twice and experience both pain and depression? As unfair as it feels, scientific studies suggest that something in my biology predisposes me to having both conditions. Pain and depression can unleash a vicious cycle in which each condition continually worsens the other. Furthermore, these conditions are similar at a biological level: under normal conditions, our senses and emotions are managed by many of the same brain regions. When things do go wrong, be it pain or depression, similar or even identical changes in the brain are often observed.

Neurotransmitters are a key part of the nervous system, as these molecules are like the “words” that are “spoken” by neurons to send a message — like feelings of pain or sadness. Of the many flavors of neurotransmitters, the group known as monoamines has been strongly associated with both pain and depression. It’s thought that both chronic pain and depression can result when levels of these key monoamines are too low (Figure 3).

This idea that pain and depression are both caused by a neurotransmitter imbalance is strengthened by ample clinical studies of antidepressant medications. Antidepressants combat neurotransmitter deficiency (Figure 3), and they can be effective against both depression and chronic pain. Examples of antidepressants with proven benefits in pain management are tricyclic and SSRI antidepressants, which increase the amount of monoamines that can actively send messages around the nervous system. Intriguingly, opioids, a traditional pain treatment, may also relieve symptoms of depression but are not generally recommended due to their highly addictive nature.

Both chronic pain and depression can change the physical structure of the brain itself. For instance, reduction in the amount of brain tissue in the pre-frontal cortex, which is part of the limbic system, has been observed for both those suffering from chronic back pain and from depression (Figure 3). Unlike the changes to neurotransmitters, the decrease in brain tissue is likely an effect, rather than cause, of chronic pain or depression, but nonetheless demonstrates the similarities between the two conditions.

While researchers have identified the above links (and many more) between chronic pain and depression, as a scientist myself I understand that these are highly complex conditions and that solving them fully is a monumental task. Still, scientists are making amazing advances every day, and I remain hopeful that there will be better solutions in my lifetime.

Invisible illnesses are still real

For now, managing chronic conditions can be difficult, exhausting, and even socially alienating. Many of my acquaintances assure me that I “look so good,” and like many with invisible illnesses, I struggle to explain that looks can be deceiving. Because I don’t appear to be sick, it’s awkward to ask for assistance or accommodations. My pain, compounded by symptoms like fatigue and nausea, greatly hampers my ability to do things I used to take for granted, like carry groceries or walk across a parking lot. The people I actually confide in never assume that they can “diagnose” me: I value the people who believe my side of the story, on my own health, instead of their assumptions.

Invisible illnesses, unsurprisingly, can be difficult to detect and treat, and having more than one condition adds another layer of complexity. For people who have chronic pain and depression, it’s estimated that the depression gets missed 60% of the time. Some of the reasons for this oversight include that patients are more likely to report physical than mental symptoms, and that medical professionals are inclined to attribute reported symptoms to solely physical causes. Because the pain symptoms “mask” the potential depression diagnosis, patients and their healthcare providers end up focusing on only one half of the problem. This is problematic because patients may have less success treating chronic pain if they are not correctly diagnosed for mood disorders.

Always higher and always forward, towards a happier and pain-free future

People say that in life, only death and taxes are certain. But sometimes I worry if I should be adding pain and depression to my list. A critical challenge is that there is no one-size-fits-all solution for chronic pain or depression, individually or together.

Initially, I try prescription antidepressants. While they can be very effective for some people, they can also have severe and disruptive side effects, including but not limited to nausea, migraines, and weight gain. They can also stop working over time or never work in the first place. I don’t respond well to medications, but luckily, I do experience improvement from another widely recommended method: exercise. Exercise has well-documented benefits for both chronic pain and depression, and may even rival medications in effectiveness.

I also look into cognitive behavioral therapy (CBT). In this well-established strategy, therapists train patients to avoid negative thoughts and emphasize positive thinking. CBT may sound simple, but clinical outcomes show that CBT is a very promising treatment for pain and depression. According to brain imaging studies, CBT can actually make measurable changes to the neural circuits and brain activities that are involved in both chronic depression and pain, .

Many more options exist, which is great but also daunting. Because there’s no one guaranteed solution, finding the right treatment requires the tenacity to try many things and accept frequent disappointment. I know I’m supposed to “hang in there,” but as anyone else with a chronic condition can attest, doing so is much easier said than done.

For all those who have similar conditions, I believe we must press on while giving ourselves permission to feel disheartened at times. Living with chronic diseases is hard enough–there’s no need to pressure ourselves to be strong all the time. It’s not an easy situation, so it’s OK to feel overwhelmed. In such moments, I’m immeasurably grateful for my close friends and family, and I urge everyone to not only pursue medical options but to also find that confidant who is patient, faithful, and listens without judgment. If you are fortunate enough to be healthy, perhaps you can be that person for someone else.

Though it’s slow progress, every day I’m getting closer to where I want to be. In the meantime, I’m being a bit more careful about where I put my fingers when I’m cooking.

Emily Orwell is the pen name of a graduate student studying biology at Harvard University

Sean Wilson is a fifth-year graduate student in the Department of Molecular and Cellular Biology at Harvard University.

PSA: The first full week of October was National Mental Illness Awareness Week (MIAW).

The National Institutes of Mental Health has additional resources for those with mood disorders, including finding mental health providers in your area and affordable treatment options. If you are in crisis, you can contact the suicide prevention hotline at 1-800-273-8255 (24/7, toll-free).

Further Information:

• “Nervous system: facts, function, and diseases” by Livescience: general introduction on how the nervous system works
• General introduction to depression by the National Institute of Mental Health
• Chronic pain information page by the National Institute of Neurological Disorders and Stroke
• “The pain-depression-anxiety connection” by Harvard Health Publishing: briefly discusses how pain, depression, and anxiety are connected and also discusses potential treatments
• “Depression and pain” by Harvard Health Publishing: a more detailed discussion about  neurobiology behind pain and depression and how they are treated in combination
• “The Link between Depression and Chronic Pain,” published in the journal Neural Plasticity: a scholarly article that details the neurobiology underlying chronic pain and depression.