According to recent data from the National Health and Nutrition Examination Survey, depression affects an estimated 8.1% of adults aged 20 years and older in the United States, with rates nearly twice as high in women compared with men.1 Despite the availability of numerous antidepressant medications, a substantial number of patients do not demonstrate an adequate response to treatment. A high prevalence of treatment-resistant depression (TRD) has consistently been observed in various studies, with some findings showing rates of 50% to 70%, depending on the way TRD was defined.2
An accumulating body of research points to the role of inflammation in depression, including a link between inflammation and resistance to commonly used antidepressants. In addition, inflammation is associated with greater symptom severity, differential response to treatment, and greater odds of hospitalization in patients with MDD.
Given the high rates of nonresponse associated with currently available antidepressant drugs, Manish K. Jha, MD, assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai, New York City, suggests that “targeting inflammation may be a promising avenue to develop novel mechanistically driven antidepressants.”3 In a 2019 paper published in the Journal of Clinical Psychiatry, Dr Jha briefly reviewed anti-inflammatory treatments that may have antidepressant effects, and thus potential value in MDD treatment.3
Although nonsteroidal anti-inflammatory drugs (NSAIDs) have not shown clinical utility as monotherapy for depression, the adjunctive use of celecoxib, a selective cyclooxygenase-2 inhibitor NSAID, has demonstrated promise in several trials. A meta-analysis of 4 randomized controlled trials with a total of 160 patients reported remission rates that were 6.6 times higher among patients treated with celecoxib vs placebo. “However, use of celecoxib as antidepressant augmentation was discouraged in a previous report due to the relatively small sample size for a meta-analysis, limited geographic region for 3 out of 4 studies, and lack of peer review for 1 of the reported studies,” underscoring the need for further investigation.3
Multiple studies have demonstrated the potential value of certain nutritional supplements in MDD treatment for patients with elevated inflammatory biomarkers. Selected findings are highlighted here.3
· L-methylfolate was more effective than placebo in patients with elevated levels of C-reactive protein (CRP) compared with patients having low CRP levels.
· Eight weeks of treatment with curcumin (500 mg twice daily) was more effective than placebo in patients with MDD and with elevated levels of leptin.
· In a meta-analysis and a proof-of-concept study, eicosapentaenoic acid-predominant formulations of omega-3 fatty acids were superior to placebo and docosahexaenoic acid-predominant formulations.
“Arguably, monoclonal antibodies against proinflammatory cytokines are the most intriguing anti-inflammatory treatments for depression. These biologics allow precise targeting of specific immune pathways,” Dr Jha suggested.3 “As our understanding of the role of individual proinflammatory cytokines in pathogenesis of depression becomes clearer, these anticytokine treatments offer a path to personalized medicine.” In a randomized placebo-controlled trial of infliximab, an anti-TNF-α monoclonal antibody, the drug was not superior to placebo overall for treatment-resistant MDD. However, significantly better outcomes compared with placebo were noted in patients with CRP levels >5 mg/L, suggesting specific utility in this patient subgroup.
Several subsequent studies have found favorable results for anticytokine treatments in reducing depressive symptoms in patients with chronic inflammation. For example, one study found that brodalumab, an anti-interleukin 17 (IL-17) receptor antibody, was associated with remission rates of from 43% to 47% (vs 9% with placebo) in patients with moderate to severe symptoms at baseline.
Ongoing trials are investigating the use of various agents that may be effective in inflammation-mediated TRD, including the essential amino acid leucine, allogenic mesenchymal stem cells from human donors, the antibiotic minocycline, and the monoclonal antibody sirukumab.3 Dr Jha emphasized that clinicians should take appropriate precautions in considering the use of these agents for their patients with TRD. For example, there is a risk for opportunistic infections with anticytokine treatments, and brodalumab has been linked to 4 completed suicides in patients with psoriasis. In addition, because of the “risk of contaminants in nutritional supplements, clinicians should be vigilant about the source of these supplements and prescribe only pharmaceutical grade supplements when available,” he stated. “Finally, as none of the anti-inflammatory treatments are approved by the FDA, clinicians should restrict their off-label use to patients for whom FDA-approved treatments are either ineffective or impractical.”3
Dr Jha provided further discussion regarding the use of anti-inflammatory therapies for depression.
Psychiatry Advisor: Why is it important to investigate anti-inflammatory treatments for MDD?
Dr Jha: A substantial proportion of patients with MDD exhibit markers of immune dysregulation including elevated levels of inflammatory markers such as CRP. Emerging literature suggests that this might especially be the case for patients who improve inadequately with 2 or more antidepressants; that is, those with TRD. Thus, anti-inflammatory treatments may particularly effective in patients with TRD in whom other conventional treatments have proven to be ineffective.
Psychiatry Advisor: What are some of the most promising agents in this area thus far, and what should be the focus of future research on this topic?
Dr Jha: During the last 2 decades, the availability of monoclonal antibodies has tremendously improved our ability to precisely target the immune system. Thus, these are currently some of the most promising agents. A key barrier, however, is our limited understanding of when to use them. For example, although elevated levels of IL-6 are commonly reported in patients with MDD, a recent study did not find any significant difference in reduction in depression severity with anti-IL-6 monoclonal antibody vs placebo. Thus, future research should focus on characterizing the nature of immune dysregulation in MDD, identify the intermediate mechanisms (such as dysfunction of the blood-brain barrier), and develop better tools to measure changes in symptoms and function.
Psychiatry Advisor: What are the relevant treatment recommendations for clinicians?
Dr Jha: Clinicians should remain vigilant for comorbid conditions; for example, autoimmune disorders that may cause inflammation and reduce the likelihood of improvement with conventional antidepressants.
Multiple reports have now shown that elevated CRP predicts poorer response to selective serotonin reuptake inhibitor antidepressants. Thus, clinicians may consider measuring CRP in their clinical practice to guide antidepressant selection. [Editor’s note: As stated in his paper, a “recent report found a very high correlation (coefficient = 0.855) between plasma and cerebrospinal fluid levels of C-reactive protein (CRP), suggesting that peripheral measures of inflammation are good indicators of central nervous system inflammation.”3]
Use measurement-based care to prospectively identify patients with TRD by measuring symptom severity at each visit and routinely optimizing the treatment regimen based on improvement and adverse effect profile. Anti-inflammatory treatments should be considered after conventional TRD-specific treatments have proven to be ineffective.
2. Murphy JA, Sarris J, Byrne GJ. A review of the conceptualisation and risk factors associated with treatment-resistant depression. Depress Res Treat. 2017;2017:4176825.
3. Jha MK. Anti-inflammatory treatments for major depressive disorder: what’s on the horizon? J Clin Psychiatry. 2019;80(6):18ac12630