Depression is a major contributor to the overall global burden of disease, with more than 300 million individuals suffering from depression.1 Yet, the limited scope of therapeutics for the condition has left patients with few treatment options and low rates of remission. This may change as progress is made on the pathophysiology of depression. Indeed, a complex link has been found between depression and inflammation, with approximately 33% of individuals with major depression showing increased levels of peripheral inflammatory biomarkers.2

The Depression-Inflammation Link

According to Michael Irwin, MD, director of the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, who conducted a review of novel neuroimmunologic therapeutics in depression with Michael Roman, MD, from the University of Pennsylvania Psychiatry Program in Philadelphia,3 “There has been much research supporting the association between depression and inflammatory factors within the innate immune system. In several prospective and experimental studies, activation of the inflammatory processes appears to drive increases in depression in a subset of individuals, especially women. In multiple other studies, researchers have identified increased levels of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, as well as elevated concentrations of acute phase proteins in individuals with depression.”

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The duo also found animal models supporting the depression-inflammation link, with evidence that immune activation can produce depression like behaviors in repeatedly stressed animals.3 Moreover, studies have shown a positive correlation between inflammatory somatic diseases and increased risk for depression. For example, a Danish cohort study of 91,637 patients found a 45% and 63% increased risk of depression in patients hospitalized for autoimmune disorders and infections, respectively. 4 

Not only are inflammatory factors involved in the pathophysiology of depression, but they also have implications for treatment. In particular, people with depression have been shown to have abnormal increases in various markers of pro-inflammatory activity, such as cytokines IL-6 and TNF-α, and this can predict poor response to selective serotonin reuptake inhibitors.5 Suppression of these pro-inflammatory markers in individuals with depression could be critical for recovery.

Neuroimmunologic Therapeutics for Depression

“There are various neuroimmunologic therapeutics under investigation for the treatment of depression, all with unique mechanisms of action,” said Dr Irwin. “One example is nonsteroidal anti-inflammatory drugs (NSAIDs), which are cyclooxygenase (COX)-1 and -2 inhibitors. Studies investigating the efficacy of NSAIDs have shown mixed results, while NSAID augmentation therapy (the use of NSAIDs to augment mainstream antidepressant treatments) has produced more positive results, with studies showing greater therapeutic efficacy of combination therapies compared to antidepressant and cytokine monotherapies.”

Antagonisms of cytokines such as TNF-α is another treatment option because of their role in the neuroinflammatory pathophysiology of depression. However, according to Dr. Irwin, “Studies involving the antagonism of inflammatory cytokines have been inconclusive to date. Nevertheless, it appears that treatment with cytokine antagonists can improve depressive symptoms in patients with inflammatory conditions such as psoriasis, although these effects might be related to improved quality of life and remission of the inflammatory disorder.”

Ketamine has also been explored, with studies showing a rapid antidepressant effect in patients with major depressive disorder.6 Dr Irwin notes that, “Ketamine is a noncompetitive N-methyl-aspartate receptor antagonist with a complex mechanism of action. It has been shown to decrease indoleamine 2,3 dioxygenase and the kynurenine/tryptophan ratio within the central nervous system (CNS). It also suppresses levels of NF-κB, a transcription factor which initiates the inflammatory cascade that is thought to play a role in the pathogenesis of depression.” Esketamine, a chemical derivative of ketamine, was approved by the US Food and Drug Administration in March 2019 for the treatment of drug-resistant mood disorders .7

In terms of novel neuroimmunologics on the horizon for the treatment of depression, there is an ongoing study on the safety and tolerability of JNJ 54175446 in patients with major depressive disorder.8  JNJ 54175446 is a purinergic and brain-permeable P2X7 receptor antagonist that modulates the extracellular mechanisms of inflammation in the CNS, peripheral nervous system, microglia, and macrophages. The phase 2 trial of the drug is scheduled for completion in 2021 .9 Another phase 2 trial by the University of Texas Southwestern Medical Center is assessing the antidepressant effect of L-leucine in patients with inflammatory conditions, building on the novel idea of using amino acids as antidepressants.10

The Safety of Neuroimmunologic Therapeutics

Most neuroimmunologic therapeutics for depression are safe, with the most common adverse effects being headaches and nausea. However, in a few cases, there are some significant risks. “TNF-α inhibitor treatment has been associated with increased risk of opportunistic infections by tuberculosis, bacterial sepsis, and histoplasmosis, and lymphoma and other malignancies have been reported in children and adolescent patients,” said Dr. Irwin. “Furthermore, a study conducted in Korea found an increased risk of intracranial hemorrhage associated with NSAID-augmented therapies. The patients were examined 30 days after treatment, and the risk was higher in men compared to women.”

Future Prospects

Although the mechanisms involved in the relationship between depression and inflammation remain to be fully understood, they represent an exciting new pathway for the diagnosis and neuroimmunologic treatment of depression in patients with inflammatory conditions.

References

1. Depression. World Health Organization. http://www.who.int/news-room/fact-sheets/detail/depression. March 22, 2018. Accessed October 21, 2019.

2. Amodeo G, Trusso MA, Fagiolini A. Depression and inflammation: disentangling a clear yet complex and multifaceted link. Neuropsychiatry. 2017;7(4):448-457.

3. Roman M, Irwin MR. Novel neuroimmunologic therapeutics in depression: a clinical perspective on what we know so far [published online September 21, 2019]. Brain Behav Immun. doi: 10.1016/j.bbi.2019.09.016

4. Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70(8):812-820.

5. O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. Psychiatry Res. 2006;41(3-4):326-331.

6. Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Mental Health Clin. 2017;7(1):16-23.

7. US Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. http://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. March 5, 2019. Accessed October 21, 2019.

8. ClinicalTrials.gov. A Study to Investigate the Safety, Tolerability, and Pharmacodynamics of JNJ-54175446 in Participants with Major Depressive Disorder. NCT02902601. https://clinicaltrials.gov/ct2/show/NCT02902601. Accessed October 21, 2019.

9. ClinicalTrials.gov. Antidepressant Trial With P2X7 Antagonist JNJ-54175446 (ATP). NCT04116606. https://clinicaltrials.gov/ct2/show/NCT04116606. Accessed October 21, 2019.

10. ClinicalTrials.gov. Rapid Antidepressant Effects of Leucine. NCT03079297. http://clinicaltrials.gov/ct2/show/NCT03079297. Accessed October 21, 2019.