Dr. Weeks’ Comment: As I clarified years ago, depression is made worse by inflammation and so an anti-inflammatory diet is the best initial treatment protocol. Anti-inflammatory seeds are the premiere healing option being safer and more effective than over the counter (OTC) drugs like tylenol, NSAIDs and aspirin. “…it has been argued that many anti‐inflammatory drugs yield antidepressant effects, indicating a group effect, which also may be present among patients with depressive symptoms not meeting diagnostic criteria for MD…”
Efficacy of anti‐inflammatory treatment on major depressive disorder or depressive symptoms: meta‐analysis of clinical trials
First published: 04 March 2019 Free Access
ABSTRACT
No study has gathered evidence from all randomized clinical trials (RCTs) with anti‐inflammatory drugs measuring antidepressant effects including a detailed assessment of side‐effects and bias.
Results
We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti‐inflammatory agents improved depressive symptoms compared to placebo as add‐on in patients with MDD (SMD = −0.64; 95%‐CI = −0.88, −0.40; I2 = 51%; N = 597) and as monotherapy (SMD = −0.41; 95%‐CI = −0.60, −0.22; I2 = 93%, N = 8825). Anti‐inflammatory add‐on improved response (RR = 1.76; 95%‐CI = 1.44–2.16; I2 = 16%; N = 341) and remission (RR = 2.14; 95%‐CI = 1.03–4.48; I2 = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias.
Conclusion
Anti‐inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow‐up, identify optimal doses and subgroups of patients that can benefit from anti‐inflammatory intervention.
Summations
- Among 36 RCTs including almost 10 000 patients, five out of six anti‐inflammatory drugs improved depression scores compared to placebo.
- Short‐term (i.e., weeks) anti‐inflammatory add‐on to antidepressants showed improved antidepressant effects in MDD without increasing the risk for side‐effects.
- The effect size for anti‐inflammatory add‐on to antidepressants was similar to the effect size of antidepressants alone, indicating the potential clinical benefit.
Considerations
- Few studies reported on side‐effects and all studies were associated with risk of bias.
- Few studies investigated biomarkers and none explored specific depressive symptoms to predict better response to anti‐inflammatory treatment.
- Hence, future studies need to include longer follow‐up and measures of inflammation (blood, CSF, and brain scans) to identify subgroups of patients with specific depressive symptoms who could be offered anti‐inflammatory treatment.
Introduction
Increasing evidence indicates that inflammatory processes can cause and contribute to the development of depression or symptoms of depression 1–4. Based on these observations, randomized clinical trials (RCTs) have explored whether anti‐inflammatory agents may have antidepressant effects and if it can be used to improve antidepressant treatment as add‐on 5–8. In particular, non‐steroidal anti‐inflammatory drugs (NSAIDs) 5 and cytokine inhibitors 6have repeatedly been associated with beneficial antidepressant treatment response, both as add‐on to antidepressants in patients with major depressive disorder (MDD) 5 and also as monotherapy in patients with a somatic disease and depressive symptoms 6. This is supported by large population‐based settings 9, and several other agents with anti‐inflammatory properties have been found to yield potential antidepressant effects 10–12.
To date, several meta‐analyses have gathered the evidence on the antidepressant effects of NSAIDs, statins, and cytokine inhibitors 13–17; however, several of these studies only investigated specific agents 13, 14, 16, 17 did not assess the risk for side‐effects 17, only included patients with MDD while excluding patients with a somatic disease and depressive symptoms 14, 16, or failed to perform a thorough bias assessment 13, 14. Furthermore, the field is evolving rapidly and several new RCTs 18–22, 11 of anti‐inflammatory treatment effects on depressive symptoms have been published since our proof‐of‐concept meta‐analysis in 2014, necessitating an updated assessment. In addition, it has been argued that many anti‐inflammatory drugs yield antidepressant effects, indicating a group effect, which also may be present among patients with depressive symptoms not meeting diagnostic criteria for MDD 13, 15, 17.
Conclusion and perspectives
The present findings show that specifically anti‐inflammatory add‐on treatment to antidepressants may have beneficial effects in patients with MDD, but also the shown effects on depressive symptoms among patients with a somatic disease are promising. NSAIDs, cytokine inhibitors, statins, glucocorticoids, and minocycline all showed antidepressant effects.However, due to large heterogeneity in most analyses and a high risk of bias, our results need to be interpreted with caution. Nonetheless, since a large proportion of patients with MDD do not respond sufficiently to antidepressant agents, treatments targeting the immune system will very likely play a role in future more personalized treatment options including measures of inflammationand the somatic comorbidity profile in the overall assessment and evaluation of the depressed patient. In order to further explore the clinical utility and define specific criteria, large high‐quality RCTs need to (i) include several measures of inflammation over time (including cerebrospinal fluid, blood, and brain scans), (ii) compare different anti‐inflammatory agents against each other, (iii) explore whether specific patient groups respond better (e.g., patients with more severe neuro-vegetative symptoms, elevated pro‐inflammatory markers, and/or comorbid somatic diseases), and (iv) investigate the optimal timing, dosages, and duration of the anti‐inflammatory treatment in order to keep the risk for adverse events at a minimum. Furthermore, based on the intriguing findings of this meta‐analysis it is also of interest with three armed studies comparing anti‐inflammatory agents head‐to‐head with antidepressants and in combination.