Can Anti-inflammatory Drugs Treat Depression? Some Promising New Evidence But Not Yet Enough

The connection between physical ailments and mood is not a new one. It is well-established that medical illness, ranging from infections to cardiovascular disease, can result in increased symptoms of depression, while depression can predispose people to become physically sick more often.  Now, a growing body of evidence shows that depression and physical illness have something important in common: inflammation.

In theory, this connection hints that medications such as NSAIDS (non-steroidal anti-inflammatory drugs) might be helpful in the treatment of depression. This article will attempt to summarize how inflammation – a generalized process affecting the whole body – can also enter into the brain and affect mood, and how anti-inflammatory medications such as NSAIDs have the potential to put a stop to this irritating scenario.

As an example of the growing evidence base on this very topic, consider this new study by a team of Danish researchers (Kohler et al, 2014). This group performed a meta-analysis (a statistical review that allows for the pooling of data) reviewing “the antidepressant and possible adverse effects of anti-inflammatory interventions” (1). Fourteen trials (6262 participants) were included in the study, ten of which evaluated the use of NSAIDs (n=4258).  The group performed a “pooled effect estimate” that suggested that anti-inflammatory treatment, particularly the NSAID celecoxib, decreases depressive symptoms without increased risks of adverse effects.    Despite the caveat that the studies included a wide range of patients on a variety of treatments (including in some cases studies combining NSAIDs and antidepressants (2)), they state that “it is possible that specific subgroups would benefit more from anti-inflammatory intervention, such as patients with low-grade inflammation or co-morbid inflammatory diseases” (1).

This study is worth noting because it captures a trend across multiple studies: anti-inflammatory medications seem to have a positive effect on depression. But how do anti-inflammatory drugs such as celecoxib exert an anti-depressant effect? In order to answer that question, it is important to understand the process of inflammation both peripherally (in the body) and centrally (in the brain).

Our immune systems are on the lookout for evidence of invaders, both real and imagined. In the presence of infection, cellular damage, or stress, the inflammatory response may be “appropriate and necessary to maintain homeostasis in the body.” However, the inflammatory response may be “inappropriate, pathological and damaging when it is reacting out of proportion to a given stimuli or reacting to the wrong stimuli” (3).   Whatever the cause, inflammation can induce “sickness behavior,” which includes many of symptoms of depression: low mood, lethargy, decreased appetite, and diminished interest in many activities (3).

The presence of concurrent peripheral inflammation and symptoms of depression (as manifested by “sickness behavior,” for example), indicates involvement ofboth systemic inflammation and central neuro-inflammation.  In order for this to happen, mediators of peripheral inflammation, such as pro-inflammatory cytokines (small proteins that participate in local and systemic inflammatory effects (3)), must be able to infiltrate the central nervous system (CNS).  Pro-inflammatory cytokines include interleukins (including IL-1 beta and IL-6) and tumor necrosis factor (TNF-alpha). Cytokines play an important role in amplifying the effects of inflammation throughout the body.

The “cytokine hypothesis” offers a model by which cytokines travel to the CNS and cause changes in brain functioning that contribute to depressive symptoms. Several mechanisms are proposed by which cytokines get into the CNS, including hitching a ride on nerves and blood vessels leading to the brain. Once in the CNS, cytokines are thought to break down and/or decrease the production of serotonin and to contribute to a “chronic stress state” marked by dysfunction of the HPA (hypothalamic-pituitary axis) and chronically elevated cortisol levels (4). Microglia, specialized cells that function as “the resident immune sentinels” of the brain, are activated by the presence of inflammatory activity and contribute to the production of even more inflammatory cytokines. Left unchecked, chronic inflammation in the CNS can destroy functional neuronal pathways by inciting those same microglia to engage in abnormal pruning of synapses, resulting in maladaptive changes to brain structure and function (3,4).

So where do NSAIDs come in? Pro-inflammatory cytokines in the CNS stimulate the breakdown of cell membranes. Cyclo-oxygenases COX-1 and COX-2) are enzymes that use these breakdown products to produce prostaglandins, leukotrienes and thromboxanes (5), which further amplify the inflammatory reaction. NSAIDs arrest this process by stopping the action of one or more of the cyclo-oxygenases. For example, celecoxib inhibits COX-2. In animal models, celecoxib has been shown to decrease pro-inflammatory cytokine production as well as to increase serotonin production (6).   All of which is considered a good thing for not only decreasing inflammation, but also for addressing concurrent symptoms of depression.

The data from the Danish group is promising, yet there are many unanswered questions. Which NSAIDs are safest and most effective, and in which patients? Should they be used alone or together with conventional antidepressants? How long should treatment last, especially since the majority of the trials were only 6 weeks in duration?

In reality, we are far from ready to make evidence-based recommendations for initiating anti-inflammatory medications for the treatment of depression.   In the absence of more data, anti-inflammatory medications should be reserved solely for the treatment of underlying inflammatory-based medical conditions.   But it is intriguing to consider the possibility that for such patients, their NSAID is addressing both physical and emotional symptoms.

Susan Stern, M.D.