Non-steroidal anti-inflammatory drugs and efficacy of antidepressants in major depressive disorderNon-steroidal anti-inflammatory drugs and efficacy of antidepressants in major depressive disorder best-known example is the activation of the hypothalamus-pituitary-adrenal axis and cortisol secretion; however more recent studies have majro increased salivary prostaglandins and plasma acute phase proteins in depressed patients. To date best test cycle for beginners randomised controlled trials have used celecoxib or rofecoxib as adjuncts to serotonin selective reuptake inhibitors in the treatment of depression. Interpretation of these results is limited by the small sample size and short duration of these preliminary studies. The research only considers depressed patients receiving treatment in secondary care; no study disorfer examined the effectiveness of NSAIDs as an adjunct in primary care, even though most cases of depression in the UK are managed in the community by general practitioners. The study will enrol participants from general practices who have a moderate or no-nsteroidal, current or recurrent major depressive episode when medication with an SSRI is considered.
Nonsteroidal anti-inflammatory drugs NSAIDs and paracetamol have been shown to yield the potential of adjunctive antidepressant treatment effects to selective serotonin reuptake inhibitors SSRIs ; however, when investigating treatment effects of concomitant use, simultaneous evaluation of potential adverse events is important. Among , SSRI users follow-up: Low-dose acetylsalicylic acid reduced the risk of psychiatric contact in general [0. Ibuprofen reduced the risk of psychiatric contacts [0.
Concerning safety, paracetamol was associated with increased mortality [3. Especially low-dose acetylsalicylic acid may represent an adjunctive antidepressant treatment option. The increased mortality risk of concomitant use of paracetamol needs further investigation. Findings from animal and human studies are partly contradictory. Therefore, we performed a longitudinal population-based cohort study of incident SSRI users with adjustment for important confounders, such as clinical and socio-demographic factors.
Additionally, if concomitant NSAID or paracetamol use changed the rates of somatic adverse events and mortality. Due to data access regulations, it was not possible to access the entire population. N06AB between January 1, , and December 31, without antidepressant use in the year preceding the date of SSRI treatment initiation index date.
Each individual was only included once. Prescription durations were calculated based on the prescribed number and strength of pills and the Daily Defined Dose DDD World Health Organization for every drug because direct prescribed dosage information was not available. To account for compliance issues and differences in drug dosages across indications, the calculated treatment length was extended.
Follow-up started on the index date. Disorders due to use of alcohol, disorders due to use of substance use, schizophrenia spectrum, bipolar disorder, depression, anxiety disorders, and all other remaining psychiatric disorders diagnoses codes provided in Table S1.
The Charlson score was categorized into 0, 1, 2 and 3 or more depending on the number of comorbid somatic diseases. Socio-demographic factors included gender, age, and educational level. Age-groups were divided into: We used time since index date as underlying timescale with age as a continuous variable. Linear splines were applied and we included all potential covariates in the models: Gender; educational level; use of NSAIDs, paracetamol, other anti-inflammatory or GI-protective drugs within the year prior to index date; previous contacts with psychiatric and somatic disorders; Charlson Index Score; earlier suicide attempts; and start year with SSRI treatment.
In addition, we performed several sensitivity analyses. In a second and third analysis, we performed age- and sex-specific subgroup analyses.
As selective COX-2 inhibitors were available only during the period — and partially withdrawn in , a fourth sensitivity analysis on these time-periods was performed i. A fifth analysis consisted of all SSRI users suffering from a disease of the musculoskeletal system or connective tissue, as these patients are more inclined to take their prescribed NSAID medication. We further identified SSRI users with a diagnosis of rheumatoid arthritis M00—M19 and or use of allopurinol and repeated all analyses.
As prior psychiatric contacts could increase the risk for subsequent psychiatric contacts, we performed all analyses on SSRI users without any prior psychiatric contacts in a seventh analysis. In an eighth and final analysis, we performed a sensitivity analysis on incident NSAID and paracetamol users i.
To illustrate the cumulative hazard over time, we graphed cumulative incidences based on competing risk analyses, as death is a competing risk to all other outcomes, that is the risk for psychiatric contacts could be decreased because of an increased mortality risk. We identified , individuals initiating SSRI treatment between and total follow-up time: Of SSRI users, 21, Paracetamol use decreased risks of any psychiatric contact, with depression and suicide attempts.
A more than three times increased mortality risk was observed for paracetamol in combination with SSRIs. Salicylates decreased risks of any psychiatric contact and with depression, whereas both NS-COX and selective COX-2 inhibitors were associated with increased risks. All analyses were adjusted for the presence of comorbid somatic disorders related to indications for NSAID or paracetamol use and by using the Charlson comorbidity index.
This was independent of the fact if the Charlson comorbidity index was used or if the analyses were individually adjusted for all 19 diseases included in the Charlson Index. Moreover, comorbid somatic disorders had no independent impact on antidepressant treatment outcomes results not shown , but on mortality outcomes in a dose—response relationship.
Concomitant ibuprofen decreased the risk of psychiatric contacts. Diclofenac furthermore yielded a four times higher risk of contacts with depression. All other sensitivity analyses supported results from the primary analyses. We report that concomitant consumption occurs frequently on the population level. The investigation of individual NSAIDs, however, emphasized the heterogeneous effect of this therapeutic class; low-dose ASA and ibuprofen were associated with adjunctive treatment effects while paracetamol and the selective COX-2 inhibitors yielded an increased mortality risk.
However, indication for prescription was not available and low-dose ASA is often prescribed prophylactic in primary or secondary prevention of cardiovascular disease, potentially resulting in better preventive care and attention in general, which partly could explain the observed effects.
Two new and potentially important discoveries emerged from this study. Second, paracetamol in combination with SSRIs was related to a more than twofold increased cardiovascular mortality in our study compared to a 1. Although the interaction between paracetamol only and the combination with SSRIs was not addressed in the current study, our findings add concern to a possible risk for cardiovascular adverse events among users of SSRIs in combination with paracetamol despite the findings of decreased risks of any psychiatric contact, with depression and suicide attempts.
The entire group of selective COX-2 inhibitors showed an increased mortality risk and no adjunctive antidepressant treatment effects. The difference to our findings may originate in different aspects. The increased risk for suicide attempts was only based on five individuals among celecoxib users.
Thus, other psychiatric disorders may have contributed to the increased risk for psychiatric contacts observed in the current study. The authors recommended a carefully balanced use of anti-inflammatory agents in patients suffering from depression. Depression is often comorbid with painful conditions Manning and Jackson , why many require this combination therapy. However, confounding by indication should always be kept in mind.
Celecoxib may preferably be prescribed to patients with increased GI risk-profiles, possibly explaining the observed increased GI mortality. Regarding our findings of decreased risks for GI contacts among NSAID users, we investigated if these findings depended on baseline risk factors.
Previous studies that found increased risks for GI bleedings have investigated individuals without these risk factors, for example, excluding patients with cancer or prior GI bleeding events, and included more men and older individuals compared to our study de Abajo and Garcia-Rodriguez Subanalyses of our data revealed that the decreased risk was driven by individuals with prior GI drug use: Whereas, among individuals without prior GI drug use, risk for GI contacts was increased 2. This is in accordance with previous findings of limited increased risks among users of proton pump inhibitors de Abajo and Garcia-Rodriguez We investigated the entire group of NSAIDs on both effectiveness and safety measures, which is highly important because of the heterogeneity of this drug-group and as many patients rely on this combination therapy due to comorbidity Manning and Jackson However, several sensitivity analyses supported our results.
Though our findings concerning low-dose ASA are encouraging, they should still be interpreted cautiously as a higher CVD risk could be observed, potentially due to confounding by indication. Regarding the risk for confounding by indication, it has to be stressed that the indications for NSAIDs are generally somatic disorders, for example, pain for ASA, ibuprofen, and diclofenac and low-dose ASA for cardiovascular prevention.
Only redeemed prescriptions are registered, why it is not known whether the medications were actually consumed or other over-the-counter OTC medications used concomitantly. Due to lack of power the risk of completed suicide could only be assessed in users of NSAIDs in general and paracetamol.
Furthermore, the exact cause of death may not always be available or registered correctly as autopsies are rarely performed Helweg-Larsen Our results suggest that specific NSAIDs, such as ibuprofen and especially low-dose ASA, may imply a novel antidepressant treatment approach supporting increased efforts to conduct randomized clinical trials. While celecoxib showed adjunctive effects in randomized controlled trials, it was associated with an increased risk of mortality and psychiatric contacts in the current study.
The findings concerning an increased cardiovascular mortality risk for paracetamol should be investigated further. However, all these findings have to be evaluated carefully due to the risk for confounding by indication.
The current evidence neither supports nor discourages NSAID or paracetamol add-on treatment to antidepressants, why no straight forward conclusions concerning clinical advice or guidelines can be drawn.
More research is necessary to investigate which NSAIDs contain adjunctive antidepressant properties and to identify subgroups of patients that could benefit of this intervention. Furthermore, the authors thank H. The other authors declare no conflict of interests. National Center for Biotechnology Information , U. Journal List Brain Behav v. Published online May Funding Information The work was supported by an unrestricted medical student research grant from the Lundbeck Foundation.
Brain and Behavior published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Background Nonsteroidal anti-inflammatory drugs NSAIDs and paracetamol have been shown to yield the potential of adjunctive antidepressant treatment effects to selective serotonin reuptake inhibitors SSRIs ; however, when investigating treatment effects of concomitant use, simultaneous evaluation of potential adverse events is important.
Antidepressants, depression, epidemiology, mood disorders, pharmacoepidemiology, pharmacotherapy. Dose and duration of treatment Prescription durations were calculated based on the prescribed number and strength of pills and the Daily Defined Dose DDD World Health Organization for every drug because direct prescribed dosage information was not available.
Time at risk and follow-up Follow-up started on the index date. Effectiveness Any hospital contact, including outpatient visits, due to any psychiatric disorder in the secondary healthcare system.
Completed suicide and suicide attempts as two independent outcomes. Results We identified , individuals initiating SSRI treatment between and total follow-up time: Open in a separate window. Contact with any other psychiatric disorder than the others mentioned. NSAIDs are classified as: In addition, prior use of paracetamol is shown. Age; gender; educational level; previous contacts with psychiatric and somatic disorders; Charlson Index score; prior use of NSAIDs, paracetamol, other anti-inflammatory and GI-protective drugs within the preceding year to index date; SSRI start year, and earlier suicide attempts.
Age; gender; educational level; previous contacts with psychiatric and somatic disorders; Charlson Index score; prior use of NSAIDs, paracetamol, other anti-inflammatory and GI-protective drugs within the preceding year to index date; SSRI start year and earlier suicide attempts.
Conclusion Our results suggest that specific NSAIDs, such as ibuprofen and especially low-dose ASA, may imply a novel antidepressant treatment approach supporting increased efforts to conduct randomized clinical trials. Conflict of Interest Dr. Supporting Information Table S1.