Targeting Inflammation Through Cytokines to Treat Depressive Symptoms

Therapies for major depressive disorder (MDD) continue to be elusive for nearly a third of patients, particularly those with autoimmune disease comorbidities.¹ Even those whose symptoms are treated initially may endure chronic relapses of depression, the leading cause of disability worldwide.¹ Emerging evidence is suggesting that by blocking certain inflammatory cytokines, a subset of patients with refractory MDD could be successfully treated.¹

“Clinicians should consider the possibility that disturbances in the inflammatory system may be relevant to the symptoms of mental illness, like depression, comorbidity, and maybe even treatment response,” said Roger S. McIntyre, MD, FRCPC, professor of psychiatry and pharmacology at the University of Toronto in Ontario, Canada. “Hence, clinicians should ask patients about sleep disruption, obesity, childhood adversity, and dietary patterns, all of which affect inflammation.”

Inflammation-Induced Sickness Behavior Is Akin to MDD

One of the associations between inflammation and MDD is that inflammation alone can cause lethargy, pain hypersensitivity, and decreased social interaction, collectively termed “sickness behavior,” even in people who are not diagnosed with MDD.² People with MDD exhibit similar behavior, albeit chronically. Likewise, people with MDD tend to have elevated cytokine and cortisol levels.²

“The developing research on the role of neuroinflammation in depression should provide markers that will help to characterize the underlying pathophysiology of depression, and this would lead to more targeted treatments that are tailored to each individual,” said Ronald S. Duman, PhD, professor of psychiatry and neuroscience at Yale University School of Medicine in New Haven, Connecticut. “Further studies demonstrating abnormal neuroinflammatory markers in depression and treatments that target neuroinflammation are needed to convince physicians of the impact of these pathways, particularly for patients who do not respond to typical antidepressants and are considered treatment resistant.”

Comorbidities That Share Inflammatory Similarities

The proinflammatory cytokine theory largely stems from the fact that depression shares comorbidities, such as

• cardiovascular disease,
• rheumatoid arthritis,
• diabetes mellitus type 2,
• psoriasis, and
• inflammatory bowel disease.¹

Parallel investigations have included the modification of sickness behaviors in patients injected with pro-inflammatory cytokines that altered their mood, sleep, concentration, and psychomotor activity.¹

In patients who have depressive symptoms and an inflammation-mediated concomitant disorder, comorbidity influences risk. Lawes and colleagues found in the English Longitudinal Study of Ageing (N=5328 men and women; aged 52-89 years) that men with greater inflammation and depression had a higher risk for cardiovascular mortality (hazard ratio [HR], 3.89; 95% CI, 2.04-7.44) and all-cause mortality (HR, 2.40; 95% CI, 1.65-3.48).³ Although the risk in men with high C-reactive protein alone was lower than for the combination of inflammation and depression (cardiovascular disease [CVD] mortality, HR, 2.43; 95% CI, 1.59-3.71; all-cause mortality, HR 1.49; 95% CI, 1.20-1.84), depressive symptoms, CVD, and their combination in women did not predict a significant difference in all-cause or CVD mortality.³

Livia A. Carvalho, PhD, PGCAP, FHEA, lecturer in translational pharmacology at Queen Mary University of London in the United Kingdom, emphasized that researchers and clinicians need to ask, “Do depressed individuals with inflammation differ in any way from depressed individuals without inflammation? This is because if they [do], then they may need more specific attention and treatment. My research shows that they constitute a specific group at higher risk, who need different methods for prevention and treatment.”

“Inflammation only occurs in about 30% of patients with depression, not in everyone,” Dr Carvalho cautioned. “I wouldn’t recommend clinicians to screen for inflammation to aid diagnosis of depression, but in those who have a more severe condition, such as those who present with recurrent symptoms, who are not getting better from their medications, or who have other physical or mental conditions.”

Future Research to Propel the Inflammatory-MDD Link

To test the proinflammatory cytokine theory, Khandaker and colleagues have designed one of the first randomized controlled studies that will investigate the link between use of the interleukin-6 (IL-6) inhibitor tocilizumab, indicated for treating rheumatoid arthritis, in patients with depression and low-grade inflammation.⁴ Eligible patients will have ≥3 mg/L of C-reactive protein and will be tested for depression and inflammation at baseline and days 7, 14, and 28 for cognition, behavior, and evidence of inflammation. The study will conclude in 2021.⁵

“This proof-of-concept randomized controlled trial (RCT) will examine whether inflammation, particularly IL-6, plays a causal role in depression, and whether the IL-6/IL-6R pathway could be a therapeutic target for depression,” explained Golam M. Khandaker, MBBS, MPhil, MRCPsych, PhD, a Wellcome Trust Intermediate Clinical Fellow in the Psychiatry Department at the University of Cambridge in the United Kingdom. “More RCTs such as the Insight study are needed to test whether inflammation is causally linked with depression, and whether treating inflammation can treat depression.”

Dr McIntyre agreed, “Current treatments for depression, eg, cognitive behavioral therapy, medications, lifestyle modification, all have beneficial effects on inflammation. In the future, the use of more conventional anti-inflammatory agents may be possible, but would need to be supported by rigorous control studies.”

Summary and Clinical Applicability

A growing body of evidence is uncovering the link between inflammation and depression. Part of the discovery is how autoimmune disorders influence the course of depression and may explain why after several courses of pharmacotherapy, some patients remain treatment resistant.

Limitations and Disclosures

None.

References

1. Shariq AS, Brietzke E, Rosenblat JD, Barendra V, Pan Z, McIntyre RS. Targeting cytokines in reduction of depressive symptoms: A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2018;83:86-91.

2. Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17(8):497-511.

3. Lawes S, Demakakos P, Steptoe A, Lewis G, Carvalho LA. Combined influence of depressive symptoms and systemic inflammation on all-cause and cardiovascular mortality: evidence for differential effects by gender in the English longitudinal study of ageing.  [published online September 17, 2018]. Psychol Med. doi: 10.1017/S003329171800209X

4. Khandaker GM, Oltean BP, Kaser M, et al. Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open. 2018;8(9):e025333.

5. ISRCTN Registry. http://www.isrctn.com/ISRCTN16942542.  Accessed October 15, 2018.