Anti-Inflammatory Agents in the Treatment of Depression
This article was originally published here.
Our understanding of the links between depression and inflammation continues to grow. CRP inflammation biomarkers can help guide antidepressant selection as well as inform potential adjunct therapies to improve patient outcomes, including among non-responders.
Depression is the most commonly diagnosed psychiatric disorder and one of the most common health conditions globally. Despite the availability of psychotherapeutic, lifestyle, psychopharmacological, and neurostimulation treatment options for depression, many patients do not experience remission, and even treatment responders have a high relapse rate. Our clinical understanding of what causes depression remains incomplete. Among the competing hypotheses of the etiology of depression, the role of inflammation in major depressive disorder (MDD) has garnered a lot of attention and research in recent years.
The role of inflammation in depression is of interest to clinicians, as several non-medication and medication treatments and lifestyle changes can lower inflammation levels. A “root-cause” approach to treating inflammation differs from a symptom-suppressing treatment approach that may be used to address mental illness. Several anti-inflammatory agents identified in research appear to be promising as add-ons to antidepressant therapy or as helpful agents on their own.
Laboratory testing for inflammatory markers allows for identifying individuals with an “inflammatory depression” subtype, who may benefit from personalizing the prescription of antidepressants to match their inflammation status. Given that current options for adequately treating depression are insufficient, identifying novel treatment approaches such as this are urgently needed.
Depression and Inflammation: Links Growing Stronger
Getting depressed while inflamed had a purpose in human evolution. If one had a cut a few thousand years ago, for instance, it likely made sense to retreat to the cave and let the wound heal, rather than expose that wound to environmental germs.¹
A growing body of research points to a link between inflammation and depression. Clearly, the two are associated, and most likely, we will find that inflammation can lead to depression. We already know that major depression is associated with changes in immune processes and immune activation. Laboratory testing of peripheral blood in depressed and non-depressed individuals points to a few key differences in inflammatory markers.
Inflammation does not remain limited to the body – peripheral inflammatory molecules are transmitted through the blood-brain barrier and brain cells produce inflammatory molecules.²Brain inflammation or neuroinflammation results from these peripheral molecules entering the brain and from brain cells producing inflammatory molecules.
Inflammatory Biomarkers: IL-6, CRP, TNF
A subset of patients with depression was found to have elevated levels of inflammatory cytokines and other markers of inflammation. Some of the markers most frequently identified in research include interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor (TNF).²
Clinically, the most practical blood marker for measuring inflammation in patients is CRP or hsCRP (high sensitivity CRP). HsCRP, a more sensitive form of the CRP test, is preferable to order in patients with suspected and diagnosed depression. CRP is an inexpensive test performed by most commercial laboratories. The test is becoming even more accessible as new technology has made fingerstick CRP tests available for use in medical offices. Patients can also purchase a home CRP kit through various vendors to check their level without going to a lab.³
One concern about measuring peripheral blood markers when thinking about the brain and depression is that the peripheral values may not reflect inflammation within the brain. Yet, studies have established that the two are connected. Elevated peripheral CRP values have been associated with high CRP values in cerebrospinal fluid, and established brain biomarkers of depression, including decreased corticostriatal connectivity and increased basal ganglia glutamate.⁴
Chronic Inflammation and Cardiovascular Risks
Chronic low-grade systemic inflammation is also associated with elevated CRP values and chronic elevation in CRP is associated with a higher likelihood of cardiovascular disease, stroke, and increased mortality.⁵ In people with depression, elevated CRP levels are associated with a higher likelihood of hospitalization,⁶ higher severity of depressive symptoms,⁷ and suicide.⁸ In addition, higher levels of CRP in non-depressed individuals may predict the future development of depressive symptoms.⁹
See also, the interplay between psychiatric and medical conditions.
Inflammatory Depression and Anxiety
Inflammation in the brain impacts several neurotransmitter systems, including serotonin, dopamine, and glutamate pathways. Neuroinflammation activates the kynurenine pathway, which generates the neurotoxic metabolite quinolinic acid. While our brains have a mechanism for protecting us from the negative impact of inflammation, a state of chronic neuroinflammation develops when we are overwhelmed.¹
Specifically, when talking about mental health, inflammation impacts brain regions related to depression and anxiety.¹⁰
The depression-related brain areas include:
Basal ganglia
Cortical reward
Motor circuits
and changes in those areas result in low motivation and lowered motor activity.
The anxiety-related brain regions affected by inflammation include:
Amygdala
Insula
Anterior cingulate cortex
and the impact on these areas results in changes in the arousal and alarm systems.¹⁰
Overall, inflammation-induced changes in the brain contribute to a particular subtype of “inflammatory depression.” These patients have low motivation, low activity levels and fatigue, and anxiety. Other features include disturbed sleep and appetite, medical comorbidities such as obesity, and treatment resistance to SSRIs.²˒⁴
Using CRP to Guide Antidepressant Treatment in Patients with Depression
The clinically relevant question is whether identifying inflammatory depression can guide treatment that is different and more effective? Can clinicians use CRP values to guide antidepressant choices? Research in this area is in development. However, several studies provide early clues as to how measuring CRP could help psychiatrists make better antidepressant selections.
First, the bad news – elevated inflammation predicts poor response to commonly used antidepressant medications.¹¹ In a meta-analysis of 35 studies, Strawbridge et al noted that depression treatment non-responders tended to have higher baseline inflammation and that these elevated inflammation levels contributed to treatment resistance. They identified a different biomarker, persistently elevated TNF alpha, as being predictive of treatment resistance.
Now the good news – antidepressant treatment affects the immune system and may lower inflammation. In a recent meta-analysis, IL-6 was significantly reduced after SSRI treatment but CRP was not.¹² Yet, CRP could guide antidepressant prescribing choices. Two research studies showed a benefit to using CRP to guide antidepressant selection between the SSRI and other antidepressant classes (TCAs and atypical antidepressants).
In a study published in 2014 in the American Journal of Psychiatry, Uher et al reported that patients diagnosed with depression and CRP levels less than 1 mg/L (optimal, low inflammation and lower risk CRP levels) before treatment initiation experienced a significantly greater reduction in depression symptoms with escitalopram (an SSRI) as compared to nortriptyline (a TCA).¹³ On the other hand, depressed patients with CRP levels ≥ 1 mg/L responded significantly better to nortriptyline than escitalopram.
In a 2017 study, Jha et al found that individuals with depression and lower CRP levels (CRP < 1 mg/L) responded better to escitalopram monotherapy. Those with higher CRP levels (CRP ≥ 1 mg/L) responded better to a bupropion (an atypical antidepressant ) and escitalopram combination.¹⁴Those who received antidepressant treatment guided by their CRP results had a significantly higher remission rate of 53.1%, while those who received CRP mismatched treatment had a remission rate of 30.9%.
In psychiatry, being able to help half rather than one-third of patients is meaningful. Would this CRP matched depression treatment be even more effective if the root causes of inflammation such as stress, inactivity, and poor diet were also addressed? What about adding anti-inflammatory agents?
Anti-Inflammatory Agents as Add-Ons in the Treatment of Depression
NSAIDs and Antidepressants: Joint Therapy for Depression
A 2019 meta-analysis of 26 studies with 1,610 participants showed that anti-inflammatory agents reduced depressive symptoms compared to placebo with a medium effect size. In addition, anti-inflammatory agents contributed to higher response and remission rates for both monotherapy and when added to antidepressants. The anti-inflammatories found to have a significant antidepressant effect were non-steroidal anti-inflammatory drugs (NSAIDs), omega-3 fatty acids, statins, and minocyclines.¹⁵
In this meta-analysis, all four studies on adding NSAIDs to antidepressants involved celecoxib 400 mg per day and showed a significant additional benefit to antidepressants alone. The results are impressive. Those given antidepressants plus the NSAID celecoxib had a 76% better chance of a reduction in depressive symptoms score than those given antidepressants alone. Yet, the four studies included were small, each with 32 to 40 participants, and short, each lasting 6 to 8 weeks.
A separate but related 2020 12-week RCT for bipolar depression was negative.¹⁶ So, due to the limited number of studies and methodological issues with the research, it is too early for clinicians to consider adding celecoxib to every antidepressant prescription.
Omega-3 Fatty Acids for Depression
Of the 17 studies on omega-3 fatty acids included in the 2019 meta-analysis, 8 showed a benefit for depression.¹⁵The overall benefit for depression was less impressive than that of NSAIDs, however.
Suneson et al also reviewed studies on omega-3 fatty acids for depression. Her team suggested that omegas may be particularly beneficial for a subset of patients with MDD and signs of low-grade inflammation. ³ The higher the level of inflammation, as reflected by more positive inflammatory markers, the more likely patients with depression were likely to benefit from omega-3s, particularly from the EPA rather than the DHA subcomponent of omega-3 fatty acids.
Thus, while omega-3 fatty acids may not be a robust treatment for depression for all, they appear to be clinically useful for those with inflammatory depression. Suneson et al also looked at the use of probiotics and exercise as anti-inflammatory treatments for depression. Both were found to be effective and appeared to lower inflammation. These nonpharmacological anti-inflammatory treatments may be most beneficial for those with inflammatory depression.
Overall, when thinking about using anti-inflammatory agents to help someone with depression, we need to consider the side effects. NSAIDs, statins, and minocycline all have potential side effects, with those of most concern being GI ulcers and bleeding, increased risk of heart attacks and strokes, and infections. In a review that considered the side effects of celecoxib when used for depression treatment, celecoxib did not cause an increased number of GI or cardiovascular events after six weeks, and it did not increase the risk for infections after 12 weeks of treatment compared to placebo.¹⁷ Still, chronic use of NSAIDs beyond 12 weeks may be problematic for physical health. On the other hand, addressing modifiable lifestyle risk factors such as lack of physical activity, weight, smoking, and poor diet lowers inflammation and improves physical health.¹⁸
Treating Inflammatory Depression: Professional Takeaways
Psychiatrists do not typically prescribe NSAIDs, statins, or minocycline, so the evidence will need to be quite convincing for this group of mental health clinicians to adopt prescription anti-inflammatories widely.
Of the prescription agents, celecoxib is most promising but the research is limited.
While we wait for further evidence to accumulate on prescription anti-inflammatory agents, clinicians may consider recommending non-medication approaches such as omega-3 fatty acids, probiotics, exercise, and anti-inflammatory lifestyle interventions to treat inflammatory depression.
Testing for CRP can also help psychiatrists identify patients with high inflammation levels, guide antidepressant medication choices, and identify patients who are most likely to benefit from adding a prescription or non-prescription anti-inflammatory agent. Tracking inflammation markers such as CRP may further motivate patients to embrace the anti-inflammatory lifestyle and to take on a sense of agency in addressing the root causes of their illness.
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