Cycloxoygenase-2 Inhibitors: A Novel Treatment Option for Borderline Personality Disorder?

Dear Editor,

Borderline personality disorder (BPD) is a debilitating disorder that manifests through unstable mood, behavior, and social relationships. BPD is often seen with comorbid psychiatric disorders, making its identification and treatment significantly more difficult. Pharmacotherapy such as the use of antidepressants (amitriptyline and fluoxetine), mood stabilizers (carbamazepine, valproate and lamotrigine), and atypical antipsychotics (aripiprazole, ziprasidone and olanzapine) are commonplace in BPD management. ¹ However, dialectal behavioral therapy remains the most used psychotherapy in managing BPD. ²

Inflammation and chronic stress are thought to play a key role in the pathogenesis of psychiatric disorders, including BPD. Studies have reported elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and enzymes such as cyclooxygenase-2 (COX2) in BPD ). ³ In this letter, we examine the possible role of COX-2 in the pathobiology of BPD and argue for systematic testing of the efficacy of COX-2 inhibitors for treating BPD.

COX-2 is an inducible enzyme capable of triggering inflammation. It has a high expression throughout the brain, specifically in regions severely affected in BPD, such as the cerebral cortex and the hippocampus. ⁴ Excitotoxic insults, oxidative stress, and pro-inflammatory effects in the above-mentioned areas increase the production of COX-2, resulting in BPD symptoms such as impulsivity and mood disturbances. ⁵ COX-2 exerts its pro-inflammatory actions primarily through IL-6, but it is also promoted by IL-6, inducing a positive feedback loop. By inhibiting COX-2 through COX-2 inhibitors such as celecoxib or rofecoxib, it is possible to break the positive feedback loop and reduce the inflammation. ⁶

Low doses of celecoxib have been shown to cross the blood–brain barrier and inhibit COX-2 levels throughout the brain, neutralizing neuroinflammation. Moreover, a recent animal study showed that COX-2 inhibition reduces anxiety-like symptoms common in BPD. The study also revealed an increase in excitatory glutamate currents, ⁷ which are downregulated in BPD. Moreover, amygdala activation, which is enhanced in BPD, is reduced when treated with a COX-2 inhibitor. ⁸ This underscores the importance of COX-2 inhibition in the mechanisms of lowering stress-induced neurochemical changes which is a key factor in the pathogenesis of BPD.

Though there is a lack of safety data for COX-2 inhibitors in BPD, COX-2 inhibitors have been successfully trialed in schizophrenia and bipolar disorder.^9,10 The most common adverse effects affected gastrointestinal or cardiovascular systems, with incidence rates not significantly different from placebo. ¹¹ This suggests that COX-2 inhibitors may be safe to test in BPD. However, the clinical course of BPD is continuous with periodic exacerbations, as opposed to mood disorders conventionally viewed as having an episodic course. Given these differences, future studies will need to identify the right time to initiate treatment as well as the duration of therapy with COX-2 inhibitors and anti-inflammatory compounds in BPD. Specifically, it would be meaningful to investigate whether they will be more useful in the acute phase of symptoms in BPD or even during relative clinical stability.

To conclude, given the increasing research attention on inflammatory processes in the pathogenesis of psychiatric disorders, the lack of relevant interventional literature on BPD is rather surprising. We aim to draw researchers’ attention to this unexplored area, which may also throw more light on the pathogenesis of BPD. We also make a pitch for more interventional trials using COX-2 inhibitors in BPD to delineate symptom phenotypes where this approach may be more relevant. Till such high-quality evidence is available, retrospective chart reviews of BPD patients treated with COX-2 inhibitors may be used as preliminary evidence to inform practice and study the role of COX-2 inhibitors in BPD.