An older woman with severe treatment-resistant depression has not responded to multiple antidepressant and augmentation trials or to ECT. She functions poorly on a daily basis and complains of insomnia, poor appetite, and a “brain fog,” or unclear thinking. In addition, she has had a history of breast cancer, currently in remission after chemotherapy, with subsequent development of fibromyalgia, rheumatoid arthritis, chronic fatigue, and chronic pain. Would the use of anti-inflammatory drugs be indicated for augmentation of her antidepressant treatment given a large number of comorbid inflammatory conditions?

Reply from Helen Lavretsky, M.D., M.S.

Your question brings up an important issue of the inflammatory mechanisms of treatment-resistant depression in older adults, especially in those with known comorbid inflammatory conditions.

Inflammatory processes, typically stress-related, have been implicated in late-life depression, anxiety, insomnia, cognitive decline, and Alzheimer’s disease (1). Aging is accompanied by a two- to fourfold increase in plasma/serum levels of inflammatory mediators such as cytokines and acute phase proteins. In addition, chronic inflammatory processes are implicated in diverse health outcomes associated with aging, such as atherosclerosis, insulin resistance, diabetes, and metabolic syndrome. Furthermore, there is some evidence that aging is associated with a dysregulated cytokine response following stimulation. Consistent with this research, inflammatory mediators are strong predictors of mortality independent of other known risk factors and comorbidity in elderly cohorts. For example, IL-6, a proinflammatory factor whose concentration generally increases in the blood with age, has been linked with Alzheimer’s disease, depression, osteoporosis, rheumatoid arthritis, cardiovascular disease, and some forms of cancer, and it is prospectively associated with general disability and mortality in large population-based studies (2, 3). Anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) may actually confer a protective role for the immune system, involving phagocytosis of dying neurons and processing of beta-amyloid and microglia that have been implicated in late-life neuropsychiatric disorders. These cytokines may be particularly important in conferring increased resilience to the inflammatory response. However, prevalence of geriatric depression is higher among those with insomnia, medically ill patients in medical settings, and in long-term care. Additional stress-inducing circumstances of acute or chronic medical illness, insomnia, or chronic pain may also be associated with depression that is relevant for this patient.

To support this, a recent paper from Elderkin-Thompson and colleagues (4) identifies the relationship between circulating proinflammatory cytokines and cognitive performance in 87 depressed elderly and comparison healthy subjects in a cross-sectional study. Encoding and recall were inversely associated with IL-6 levels in both groups after controlling for chronological age, MMSE, body mass index, literacy level, depression severity, and sex. C-reactive protein (CRP) was not associated with cognition. Depression was associated with poor recall independent of IL-6. The authors concluded that IL-6 serum levels among old individuals with or without depression can be a significant correlate of memory performance. Women in particular appear sensitive to IL-6 fluctuations among both groups that support the notion of women being more vulnerable to stress. These findings support prior literature on the relationship between inflammation and cognitive decline. The link between memory ability and cytokine can occur at the molecular level via cytokines’ role in neurogenesis, memory consolidation, and synaptic plasticity.

Researchers are starting to address the potential role of anti-inflammatory drugs in management of treatment-resistant depression in late life. An interesting report from a large Australian cohort of 3,687 men aged 69–87 years by Almeida and colleagues (5) suggested that men with high levels of plasma homocysteine may have decreased risk of depression if they are using aspirin as an anti-inflammatory antiplatelet preventive strategy. In the recently published study by Raison et al. (6), a double-blind randomized trial of repeated infusions of the TNF antagonist infliximab, 5 mg/kg, (N=30) versus placebo (N=30) in patients with treatment-resistant depression found no overall difference in change of HAM-D scores between treatment groups across time. However, exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/liter revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (N=8 of 13 patients) in infliximab-treated patients versus 33% (N=3 of 9 patients) in patients receiving placebo. This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. This and other new evidence would support the use of anti-inflammatory drug use in management of treatment-resistant depression. However, in the absence of more convincing evidence and concerns about toxicity and drug-drug interaction, the use of NSAIDs in treatment-resistant depression is still experimental and should be reserved for patients with the underlying inflammatory diseases requiring administration of these drugs.

Frequently, older adults are not able to tolerate anti-inflammatory drugs due to multiple side effects. Integrative medicine (7) has long recognized the potentially harmful effects of anti-inflammatory drugs on inflammation in the gut or “leaky gut syndrome” due to increased intestinal permeability leading to increased inflammation in the body. In addition, drug-drug interaction between NSAIDs and SSRIs can reduce antidepressant efficacy as well as potentially increase gastrointestinal bleeding risk (8). Nonpharmacological mind-body approaches (e.g., yoga and Tai Chi/Qi Gong) have been used to reduce stress and inflammation that could serve as a useful alternatives to drug use. Irwin and Olmstead (9), Lavretsky et al. (10), and Black et al. (11) documented benefits of mind-body interventions in older adults with and without depression in decreasing peripheral plasma levels of inflammatory factors, and downregulating gene expression in the inflammatory pathways. The authors concluded that Tai Chi Chih, yoga, and similar mind-body practices could be considered as a useful behavioral intervention to reduce circulating levels of inflammatory factors in older adults who are at risk for inflammatory morbidity.

Optimal management of the underlying medical conditions, sleep, and chronic pain are likely to improve inflammation and may lead to an improved antidepressant response. In addition, cognitive behavioral psychotherapy or interpersonal psychotherapy can be recommended for management of ongoing life stressors and coping with chronic illness.