illustration of the gut brain connection related to depression
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Summary: Yes, studies show a clear association between inflammation and depression. However, there’s no clear consensus about whether the association is strong enough to consider inflammation as a specifier for clinical diagnosis of major depressive disorder (MDD).

Key Points:

  • Evidence shows a significant percentage of people with depression have elevated biomarkers for inflammation
  • Inflammatory biomarkers appear in brain areas associated with symptoms of depression in people diagnosed with MDD
  • After ruling out the influence of lifestyle factors and pre-existing medical conditions, research shows the connection between inflammation and depressive symptoms remains significant.

New Perspectives on Inflammation and Depression

Over the next several years, the American Psychological Association (APA) will release the Diagnostic and Statistical Manual of Mental and Behavioral Disorders, Volume 6 (DSM-6), which will be the newest version of the go-to diagnostic reference for the clinical diagnosis of mental illness, behavioral disorders, and associated pathologies. The DSM-6 follows the DSM-5, published in 2013, and the DSM-5 Text Revision (TR), published in 2022.

The APA has not specified a specific release date for the DSM-6, but experts expect it to appear before 2028.

As the APA collects the input of expert mental health providers, researchers, and scientists to complete the DSM-6, the contributors engage in a robust debate about the changes needed to ensure clinicians are well-prepared to meet patient needs as we move forward into the 21st century.

Important topics on deck for the DSM-6 include:

  • A revision of the diagnostic criteria for and definition of autism spectrum disorders (ASD).
  • Consideration of internet use behaviors that resemble the disordered use of substances, commonly called addiction, in addition to internet gaming disorder (IGD), the only clinical diagnosis for internet addiction recognized in the DSM-V and DSM-V (TR).
  • The role of telehealth and virtual therapy in best treatment practices for mental health

In addition to the standard process of review, mental health professionals with strong viewpoints on the development of the new DSM-6 offer their input in the form of public editorials and position papers published in reputable sources like the Journal of the American Medical Association: Psychiatry (JAMA Psychiatry).

Here’s a recent JAMA Viewpoint release that got our attention:

“Should Inflammation Be a Specifier for Major Depression in the DSM-6?”

That’s an interesting question, and touches on aspects of mental health treatment gathering momentum in the 21st century, such as the impact of disparate factors such as lifestyle and genetics on the development, symptomology, and treatment of depression.

Let’s review the relevant data on inflammation and depression and learn more about the current state of knowledge on the topic.

Inflammation and Depression: What’s a Specifier?

Here’s a simple definition of the term specifier:

“Specifiers provide a means of establishing sub-categories or variations, particularly within mood disorder diagnoses, and supply tools for mental health professionals to offer more accurate diagnoses and design targeted treatment options.”

For instance, if a patient receives a diagnosis of major depressive disorder (MDD) with one of the flowing specifiers, the diagnosis would be MDD with:

  • Anxious distress
  • Mixed features
  • Melancholic features
  • Atypical features
  • Psychotic features
  • Peripartum onset
  • Seasonal pattern

A full diagnosis with a specifier might read MDD with anxious distress or MDD with seasonal pattern. These specifiers are evidence-based, meaning they occur frequently enough among people with depression that identifying them in a clinical diagnosis can help define an appropriate and effective course of treatment.

Therefore, the question at hand is this: is inflammation a significant enough factor in enough people with depression to qualify as a helpful specifier?

Let’s take a look.

The Evidence for Inflammation as a Depression Specifier

A growing body of research indicates significant connections between inflammation and depression, with the following areas of research suggesting inflammation may be a viable specifier in the upcoming DSM-6:

1. Inflammatory Biomarkers in People with Depression

At least three studies – including Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications, Genetic Contributions of Inflammation to Depression, and Association Between C-Reactive Protein (CRP) With Depression Symptom Severity and Specific Depressive Symptoms in Major Depression – show the following elevated biomarkers in people with depression:

    • Cytokines in the interleukin (IL) class: IL-1-beta, IL-6, and others
    • Tumor necrosis factor (TNF)
    • C-reactive protein (CRP)
      • 25% of patients with depression show high CRP

In addition, a study using data from the UK Biobank showed high CRP was associated with increased risk of the following depressive symptoms, associations that remained significant after accounting for the influence of lifestyle factors including body mass index, smoking tobacco, alcohol consumption, and physical activity:

    • Anhedonia, i.e. low mood, inability to experience pleasure
    • Fatigue: chronic low energy
    • Psychomotor slowing: reductions/disturbances in speech, thought, fine motor skills, and general movement
    • Impaired appetite/changes in appetite
    • Disturbed sleep: sleeping too much, i.e. hypersomnia

2. Inflammation Affects Neurotransmitters in Brain Areas Associated with Depression

Evidence indicates elevated inflammation can have an impact on the following:

    • Synthesis, signaling, release, and reuptake of dopamine
    • Dopamine function in brain areas associated with reward
    • Dopamine function in brain areas associated with motivation
    • Functional connectivity between brain areas associated with reward and motivation

3. Inflammatory Biomarkers and Treatment Response

A study conducted in 2020, Inflammatory Proteins and Clinical Response to Psychological Therapy in Patients with Depression: An Exploratory Study, showed that elevated presence of the following inflammatory biomarkers was associated with a decreased, low, or poor response to standard treatment for depression:

    • Tumor necrosis factor (TNF)
    • Interleukin-6 (IL-6)
    • Soluble intracellular adhesion molecule-1 (slCAM-1)

After treatment, patients who didn’t respond well to treatment show persistent elevated levels of:

    • C-reactive protein (CRP)
    • Thymus and activation regulated cytokine (TARC)
    • Macrophage chemoattractant protein-4 (MCP-4)

The number of studies connecting inflammation and depression confirm there’s a definite relationship between the two, but to date, there’s no consensus on adding inflammation as a specifier for depression in the new DSM-6.

Inflammation and Depression: Genetics, Lifestyle, or Both?

In a response to the JAMA Viewpoint release on adding inflammation as a specifier for depression in the new DSM-6, an experienced biomedical researcher recognizes that while evidence does indeed establish clear connections between inflammation and depression, the strength of the evidence does not yet justify its inclusion as a clinical specifier.

What’s unclear, to date, is not the connection of inflammation and depression, but whether the presence of elevated inflammatory biomarkers can predict the development of depression and response to depression treatment in a large enough percentage of the population to warrant its inclusion as a clinical specifier.

Currently, more research is needed to distinguish between lifestyle and genetic contributions to inflammation in patients with depression.

How Would an Inflammatory Biomarker Test for Depression Help?

Using blood tests – rather than subjective self-report questionnaires and/or clinician-administered questionnaires supported by observation – to diagnose mental health disorders is a long-term, big picture goal for mental health providers.

Any objective measure with quantifiable results would improve diagnostic accuracy, and therefore, improve our ability to create treatment plans that meet patient needs.

If the DSM-6 includes an inflammation specifier for depression, the inflammatory biomarkers identified for testing need to meet at least three criteria:

  • Available and measurable under standard conditions across lab types
  • Predetermined values for levels of inflammation, i.e. above/below cutoff points
  • Must be supported by evidence across a wide variety of peer-reviewed studies

Several good candidates exist that meet all three criteria, with one of the most tested inflammatory biomarkers in medical practice, CRP, the most likely candidate.

However, a diagnosis of major depressive disorder with inflammation does not yet exist. If further evidence shows the presence of inflammatory biomarkers such as CRP can predict the development of MDD compared to a control group without CRP biomarkers, and further research confirms the finding that elevated CRP predicts poor treatment response, then we may see this specifier – MDD with inflammation – in the DSM-6 when it arrives.

This could help providers design treatments that account for inflammation not only in depression, but in various mental health contexts. Here’s how the author of the JAMA Viewpoint views the potential benefits of adding an inflammation specifier for depression:

“Such a specifier, even if designated primarily for research purposes, would provide a large database for further refining clinical phenotypes, blood-based biomarkers, and treatment responses, ultimately supporting precision psychiatry and guiding clinical care.”

As we learn more about the relationship between inflammation and depression, and the relationship between inflammation and general health, the diagnostic tools scientists develop may help us identify and resolve the negative consequences associated with inflammation, and thereby improve our mental health, physical health, and overall wellbeing.

Finding Support: Resources

If you or someone you know needs professional treatment and support for depression, please contact us here at Crownview Psychiatric Institute: we can help. In addition, you can find support through the following online resources:

About Angus Whyte

Angus Whyte has an extensive background in neuroscience, behavioral health, adolescent development, and mindfulness, including lab work in behavioral neurobiology and a decade of writing articles on mental health and mental health treatment. In addition, Angus brings twenty years of experience as a yoga teacher and experiential educator to his work for Crownview. He’s an expert at synthesizing complex concepts into accessible content that helps patients, providers, and families understand the nuances of mental health treatment, with the ultimate goal of improving outcomes and quality of life for all stakeholders.