Will we prescribe non-steroidal anti-inflammatory drugs for mental illness?

Neuroinflammation and oxidative stress accelerate the development of neurodegenerative diseases and aging processes. There is increasing evidence that these factors also play a role in the pathogenesis of depression. Recent studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) might alleviate symptoms of depression. A recent meta-analysis has shown that adding NSAIDs to treatment reduces symptoms of depression, improves treatment response, and increases remission rates without raising the risk of adverse effects.

Pathogenesis of depression and inflammatory processes

Research has already proven that neuroinflammation and oxidative stress significantly promote the development of neurodegenerative diseases and aging processes. Increasing evidence also shows that these factors are involved in the onset of depression. Current theories describe depression as a neuroprogressive mood disorder where cell aging accelerates, and the risk of age-related somatic diseases increases. Neuroprogression is a developing process comprising neurodegeneration, including apoptosis, decreased neurogenesis, reduced neuronal plasticity, and increased autoimmune responses. Clinicians and scientists observe these phenomena at both clinical and biochemical levels in patients with depression, evidenced by increased markers of oxidative stress and neuroinflammation markers in the blood. Various factors related to the body's inflammatory processes such as psychosocial stress, poor nutrition, physical inactivity, obesity, smoking, intestinal permeability disorders, allergies, dental caries, periodontal diseases, lack of sleep, and vitamin D deficiency all contribute to the development of depression. Additionally, these inflammatory factors are crucial in other mental disorders like bipolar disorder, schizophrenia, and post-traumatic stress disorder. At the molecular level, post-mortem examinations of the prefrontal cortex in patients with depression reveal signs of inflammation, apoptosis, and oxidative stress.

Impact of reactive oxygen species on neurons

The brain consumes more than 20% of the body’s total oxygen, and while essential, some oxygen derivatives can become neurotoxic. Reactive oxygen species (ROS) form when unpaired electrons attach to oxygen molecules, quickly oxidizing and altering RNA, DNA, proteins, and lipids, which inevitably harms neurons. Normally, the body's antioxidant defense systems regulate ROS levels. However, an imbalance between oxidants and antioxidants triggers oxidative stress. Brain cells, particularly sensitive to this harmful stress, risk damage due to their fast metabolism, numerous high-level peroxidation substrates, and low antioxidant levels.

High levels of oxidative stress biomarkers are common in individuals with depression, for instance, 8-hydroxy-2'-deoxyguanosine and malondialdehyde (MDA), indicating oxidative DNA damage and a significant reduction in antioxidant enzyme activity. Interestingly, while ROS are toxic by-products of cellular metabolism, they also serve as crucial second messengers in essential neurobiological processes such as cell growth, proliferation, migration, immune responses, gene expression regulation, and cell death regulation.

Chronic mild stress and its impact on mitochondrial function

Chronic mild stress serves as a strong trigger for depressive behavior in animals, impairing mitochondrial structures and functions in their brains, linking depression to mitochondrial dysfunction. Notably, ROS production, a by-product of monoamine oxidases, plays a vital role in the deactivation of monoaminergic neurotransmitters like serotonin, dopamine, norepinephrine, and adrenaline, which are crucial to the pathophysiology of depression.

Celecoxib study

In conducting a study on celecoxib, researchers centered on its antidepressant effects attributed to its anti-inflammatory properties, particularly its ability to inhibit pro-inflammatory cytokines such as interleukin-6 (IL-6). Forty patients with depression, each with a Hamilton Depression Rating Scale (HAM-D-17) score of 18 or higher and undergoing treatment with sertraline (200 mg/d), engaged in a randomized, placebo-controlled trial. Researchers randomly designated these participants to receive either celecoxib (200 mg twice daily) or a placebo for 6 weeks. They measured the IL-6 serum concentrations at the start and end of this period and evaluated the HAM-D-17 scores at the beginning and after 1, 2, 4, and 6 weeks.

The group receiving celecoxib achieved significant reductions in both serum IL-6 concentrations and HAM-D-17 scores compared to the placebo group. This group also exhibited better treatment responses (95%) and higher remission rates (35%) than the placebo group (50% and 5%, respectively, with p-values of 0.003 and 0.04). Early in the study, researchers found a significant correlation between serum IL-6 concentrations and HAM-D-17 scores (correlation coefficient r = 0.378, p = 0.016). Additionally, they noted a significant correlation between the reduction in serum IL-6 concentrations and the improvement in HAM-D-17 scores after 6 weeks (r = 0.673, p < 0.001).

The authors recognized the limitation of not evaluating other inflammatory biomarkers. Nonetheless, the findings led them to conclude that celecoxib's antidepressant effects might relate to its capability to reduce IL-6 concentrations, echoing earlier studies that proposed celecoxib as a safe and effective adjunct treatment for depression.

Further research proposal

Recognizing the significant link between depression and inflammatory processes, researchers have examined the antidepressant potential of NSAIDs, although the results have been varied. Additionally, the known side effects of NSAIDs can restrict their use. Pursuing this inquiry further, researchers conducted a systematic review and meta-analysis of randomized controlled trials to explore both the side effects and antidepressant effects of NSAIDs, involving 6,262 adult patients with depression. Based on the comprehensive analysis, NSAID treatment demonstrated greater effectiveness in reducing depression symptoms compared to placebo. Overall, NSAIDs improved symptoms with a mean standard deviation (MSD) of -0.34 (95% CI -0.57 to -0.11). Specifically, for patients with clinical depression, the effect was more pronounced, showing an MSD of -0.54 (95% CI -1.08 to -0.01), and for those exhibiting depressive symptoms, the MSD was -0.27 (95% CI -0.53 to -0.01). The NSAID results were also more favorable when assessing remission (Relative Risk, RR = 2.73) and treatment response (RR = 2.41).

In the context of celecoxib as an adjunctive treatment for depression, it markedly benefitted the patients compared to placebo, significantly improving both remission rates (RR 7.89; 95% CI 2.94–21.17, p < 0.001) and treatment response rates (RR 6.59; 95% CI 2.24–19.42; p < 0.001). Celecoxib's specific intervention achieved a mean standard deviation (MSD) of -0.82 (95% CI -1.17 to -0.46, p<0.001), indicating a substantial reduction in depression symptoms compared to placebo.

Despite the promising results, most studies analyzed were small-scale and short-term, with effects ranging from negligible to strong and showing considerable heterogeneity. Moreover, the potential risk of bias in these studies could have influenced the outcomes. Nonetheless, the accumulated evidence supports considering NSAIDs for the treatment of depression, underscoring the need to identify specific patient subgroups who might significantly benefit from adjunctive NSAID therapy, such as individuals with high inflammatory markers or those suffering from both depression and somatic diseases. Continued research into NSAIDs is encouraged, exploring their use as monotherapy, in combination with various antidepressants, and across different age groups, to further elucidate their therapeutic potential and safety profiles.

Summary

• Neuroinflammation and oxidative stress significantly influence neurodegenerative diseases and aging.
• Established research links depression to oxidative stress and altered antioxidant status.
• Patients with depression often show elevated markers of oxidative stress and signs of neuroinflammation.
• Recent studies indicate that NSAIDs, including celecoxib, may alleviate symptoms of depression, substantiated by detailed efficacy figures from recent meta-analyses.
• Identifying patient subgroups that could benefit from NSAID treatment is suggested, based on their inflammatory profiles and coexisting conditions.
• Ongoing comprehensive studies on NSAIDs are necessary to verify long-term effects and potential as stand-alone or combined therapy across different patient demographics.

Prepared by Dr. Alvyda Pilkauskienė

Dainava Polyclinic Mental Health Center Mental Health Day Inpatient Care

Source "Internist"