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. We investigated whether or not treatment effects of SSRIs differed depending on concomitant use of different NSAIDs or paracetamol. Additionally, if concomitant NSAID or paracetamol use changed the rates of somatic adverse events and mortality.

Findings from animal and human studies are partly contradictory. Some studies found adjunctive antidepressant effects for acetylsalicylic acid (ASA)(Brunello et al. 2006 ; Mendlewicz et al. 2006 ) and the selective COX‐2 inhibitor celecoxib (Muller et al. 2006 ; Akhondzadeh et al. 2009 ; Abbasi et al. 2012 ; Na et al. 2013 ), mostly in combination with Selective Serotonin Reuptake Inhibitors (SSRIs). Conversely, NSAIDs and paracetamol have been observed to inhibit antidepressant efficacy of the SSRI citalopram in both animal studies and a post hoc analysis of the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D)(Warner‐Schmidt et al. 2011 ). A subsequent clinical study found no association between NSAID use and modified antidepressant treatment outcome (Uher et al. 2012 ), whereas a re‐analysis of the STAR*D data found an association of decreased antidepressant treatment effect with NSAIDs in general, but not with ASA or COX‐2 inhibitors (Gallagher et al. 2012 ). These discrepancies may be a result of differential effects of NSAIDs, COX‐2 inhibitors and salicylates on antidepressant effects or confounding as pointed out by Almeida et al. (Almeida et al. 2010 ). Furthermore, potential adjunctive effects of NSAID add‐on treatment may be counteracted by increased risks of gastrointestinal (GI) bleeding episodes (de Abajo and Garcia‐Rodriguez 2008 ) and cardiovascular disease (CVD)(Schjerning Olsen et al. 2011 ), which were not considered in previous observational studies (Sandrini et al. 2002 ; Gallagher et al. 2012 ). Since antidepressants, NSAIDs and paracetamol are frequently used (Fosbol et al. 2008 ; Trifirò et al. 2013 ), it is important to further investigate whether adjunctive or adverse effects are most prominent at the population level, and beyond this to investigate the effect across the range of NSAIDs.

An inflammatory state is associated with the etiology in subgroups of depressed individuals (Benros et al. 2013 ) and an increased risk of depression (Wium‐Andersen et al. 2013 ). Thus, nonsteroidal anti‐inflammatory drugs (NSAIDs) may be used as an adjunctive treatment option against depression in combination with antidepressants (Muller et al. 2006 ; Kohler et al. 2014 ) because of common anti‐inflammatory mechanisms (Knights et al. 2010 ; Chavda et al. 2011 ), probably due to Cyclooxygenase‐2 (COX‐2) inhibition (Taler et al. 2007 ; Knights et al. 2010 ). Besides COX‐2 inhibition, other potential mechanisms of NSAIDs concerning antidepressant properties include reduction in oxidative and nitrosative stress (Anderson et al. 2013 ), prevention of increase of proinflammatory cytokines (Casolini et al. 2002 ) and increment of central serotonin levels (Sandrini et al. 2002 ). Also paracetamol may act via COX‐2 inhibition (Hinz and Brune 2012 ), but only one study has investigated the possible adjunctive effects of paracetamol (Warner‐Schmidt et al. 2011 ).

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.

In addition, we performed several sensitivity analyses. The first consisted of repeating all analyses containing the calculated versus the extended prescription duration (7 days for SSRI and 15 days for NSAID and paracetamol users). 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 1999–2006 and partially withdrawn in 2004, a fourth sensitivity analysis on these time‐periods was performed (i.e., 1997–1998, 1999–2004, and 2005–2006). 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.e., without NSAID or paracetamol use in the preceding year).

In the primary analyses, we compared SSRI users to users of the combination therapy of SSRIs and NSAIDs or paracetamol. The secondary analyses comprised investigations of specific NSAID groups and single NSAIDs in combination with SSRIs as compared to SSRI monotherapy.

COX proportional hazard regression was performed to calculate hazard rate ratios (HRR) including 95‐% confidence intervals (95‐% CI). 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.

To adjust for other anti‐inflammatory and analgesic medications, we identified use of corticosteroids (ATC‐code H02A and H02B), anti‐inflammatory/antirheumatic agents (M01B and M01C) and opioids (N02A) (23) within the preceding year. SSRIs and NSAIDs increase the risk of GI‐bleeding (de Abajo and Garcia‐Rodriguez 2008 ), why we identified prior use of H 2 ‐antagonists (A02BA), prostaglandins (A02BB), proton pump inhibitors (A02BC), helicobacter pylori eradication (A02BD), and drugs against gastro‐esophageal reflux disease (A02BX).

Psychiatric disorders (Mors et al. 2011 ) were divided into: 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). To account for somatic comorbidity (Lynge et al. 2011 ), we identified SSRI users suffering from a disorder of the musculoskeletal system or connective tissue due to the high comorbidity with pain‐causing disorders (Manning and Jackson 2013 ). The eight revision of the ICD (ICD‐8) was used until January 1, 1994, and from January 1994, ICD‐10 has been used (Lynge et al. 2011 ; Mors et al. 2011 ). Furthermore, we applied the Charlson Comorbidity Index (Charlson et al. 1987 ), which includes 19 severe chronic somatic diseases such as heart disease, diabetes, and cancer. It has subsequently been validated and used in different diseases including nonmalignant (Almeida et al. 2010 ) and depression (Thygesen et al. 2011 ) and modified for use with the ICD‐10 (Nuttall et al. 2006 ). The Charlson score was categorized into 0, 1, 2 and 3 or more depending on the number of comorbid somatic diseases.

Follow‐up started on the index date. Censoring occurred due to switching to another antidepressant drug, discontinuation of the first SSRI treatment episode, emigration, switching to another NSAID of a different class, after 3 years of follow‐up or end of the study period, whatever came first. NSAID and paracetamol use was assessed time‐varying during SSRI treatment: all individuals were for the entire follow‐up period covered with SSRIs and could concomitantly be treated with NSAIDs or paracetamol.

Prescription durations were calculated based on the prescribed number and strength of pills and the Daily Defined Dose (DDD)(World Health Organization 2008 ) 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. For SSRIs, treatment duration of every prescription was extended by 7 days, and by 15 days for prescriptions on NSAIDs and paracetamol.

Prescriptions for NSAIDs (ATC‐codes M01A and N02BA) were identified for each individual after the index date and during the preceding year. Low‐dose ASA (B01AC06) was included because it has shown additional antidepressant effects (Mendlewicz et al. 2006 ). NSAIDs were classified according to their selectivity with regard to COX‐1/COX‐2 inhibition (Knights et al. 2010 ): salicylates (i.e., acetylsalicylic acid, diflunisal, salicylamid, low‐dose ASA) due to their irreversible acetylation of COX‐1 and ‐2 enzymes; nonselective NSAIDs (NS‐NSAIDs, i.e., ibuprofen, naproxen, ketoprofen, dexibuprofen, tolfenamic acid, piroxicam) because of their nonselective inhibition of either COX‐1 or ‐2; nonselective COX‐inhibitors (NS‐COX, i.e., diclofenac, etodolac, meloxicam, nabumetone) with a more pronounced COX‐2 inhibition as compared to NS‐NSAIDs; and selective COX‐2 inhibitors (i.e., celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib). Paracetamol (N02BE01) was assessed separately, as it may attenuate antidepressant treatment (Warner‐Schmidt et al. 2011 ) and inhibit COX enzymes (Hinz and Brune 2012 ).

The study population was identified from a 25% representative random sample of the Danish population (present population approximately 5.5 million inhabitants) using the Danish Civil Registration System (Pedersen 2011 ). Due to data access regulations, it was not possible to access the entire population. Prescription drug use was assessed by linkage to the Danish National Prescription Registry (Kildemoes et al. 2011 ), which contains detailed information on each drug dispensed, but not on the indication of treatment or dosage information. We identified incident users of SSRIs (Anatomical Therapeutic Chemical (ATC) code: N06AB) between January 1, 1997, and December 31, 2006 without antidepressant use in the year preceding the date of SSRI treatment initiation (index date). Each individual was only included once.

Lower risks of any psychiatric contact and for depression was observed among users of low‐dose ASA (Table 3 , Figs 1 and 2 ), whereas the risk for CVD contacts was increased. Concomitant ibuprofen decreased the risk of psychiatric contacts. Diclofenac and celecoxib were associated with significantly increased risks of psychiatric contacts and mortality, in particular GI mortality (Tables 3 and 4 ; Figs 1 and 3 ). Diclofenac furthermore yielded a four times higher risk of contacts with depression.

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. Overall, the adjustment for somatic comorbidity had no major impact on the estimated HRRs for the association between concomitant use of SSRIs and NSAIDs and the investigated outcomes. 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. For example, the risk of all‐cause mortality, compared to no comorbid somatic disorder, was HRR=1.70 (1.39; 2.07) with 1 somatic disorder, HRR=3.56 (3.00; 4.21) with two somatic disorders, and HRR=4.57 (3.85; 5.44) with three or more somatic disorders.

Tables 3 and 4 display results for treatment effectiveness and for safety outcomes of the different NSAID groups and single NSAIDs. Salicylates decreased risks of any psychiatric contact and with depression, whereas both NS‐COX and selective COX‐2 inhibitors were associated with increased risks. NS‐COX and selective COX‐2 inhibitors increased mortality risk, whereas salicylates were associated with a higher risk of CVD contacts.

Compared to SSRI monotherapy, NSAIDs in combination with SSRIs were associated with increased adjusted risks of any psychiatric contact and with depression only (Table 2 , Figs 1 and 2 ). Paracetamol use decreased risks of any psychiatric contact, with depression and suicide attempts. Regarding side effects, NSAIDs increased risk of CVD contacts, but decreased risk of GI contacts (Table 2 ). A more than three times increased mortality risk was observed for paracetamol in combination with SSRIs.

We identified 123,351 individuals initiating SSRI treatment between 1997 and 2006 (total follow‐up time: 53,697.8 person‐years). Citalopram (58.2%) and sertraline (16.2%) were most frequently used. Of SSRI users, 21,666 (17.5%) redeemed prescriptions on NSAIDs (4.9% for low‐dose ASA, 2.6% ASA, 5.1% ibuprofen, 2.4% diclofenac, 0.5% celecoxib, and 2% for others). 10,232 (8.3%) used paracetamol concomitantly. Table 1 summarizes clinical and socio‐demographic characteristics.

Discussion

This population‐based cohort study on 123,351 SSRI users is the largest study to date on antidepressant treatment response and safety aspects of concomitant use of SSRIs and NSAIDs or paracetamol. We report that concomitant consumption occurs frequently on the population level. The combination therapy of SSRIs and NSAIDs in general yielded no adjunctive treatment effect with regard to psychiatric contacts in the secondary healthcare system. 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.

In accordance with previous nonrandomized studies (Mendlewicz et al. 2006; Almeida et al. 2012), our results indicate that low‐dose ASA could be an effective antidepressant add‐on therapy to SSRIs. 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. Clinical and animal studies support the combination therapy of SSRIs and ASA in different doses (Brunello et al. 2006; Mendlewicz et al. 2006). In individuals aged 50 or above, ASA monotherapy was associated with a reduced lifetime risk of depression (Mendlewicz et al. 2006; Almeida et al. 2012). In a recent review, the authors emphasized the antidepressant potential of ASA because of a better benefit‐risk profile as compared to other anti‐inflammatory drugs (Fond et al. 2013). Our results are in line with a recent study reporting that NSAIDs in general, but not ASA, worsened antidepressant treatment effects (Gallagher et al. 2012). In contrast, one study reported worse antidepressant treatment effects for ASA in any dose (Warner‐Schmidt et al. 2011) and another an increase in the incidence of depression in healthy men aged 69–87 using ASA monotherapy (Almeida et al. 2010). However, the uncertainty of length of concomitant use of antidepressants and NSAIDs (Warner‐Schmidt et al. 2011; Gallagher et al. 2012) may have introduced misclassification with regard to concomitant exposure.

Two new and potentially important discoveries emerged from this study. First, we showed that ibuprofen may be an adjunctive treatment approach in combination with SSRIs contrasting one prior study associating ibuprofen with inhibition of antidepressant treatment (Warner‐Schmidt et al. 2011). Second, paracetamol in combination with SSRIs was related to a more than twofold increased cardiovascular mortality in our study compared to a 1.28 times increased cardiovascular mortality risk found for paracetamol monotherapy (de Vries et al. 2010). COX‐2 inhibition may explain these epidemiological findings (Hinz and Brune 2012), but an earlier study emphasized the risk for confounding by indication (Lipworth et al. 2003). 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. This is in contrast to clinical studies, associating short‐term celecoxib add‐on treatment with antidepressant properties (Muller et al. 2006; Akhondzadeh et al. 2009; Abbasi et al. 2012) without increased CVD‐risk within the first 60 days (Solomon et al. 2006). In addition, a recent study associated COX‐2 inhibitors with slightly adjunctive treatment effects (Gallagher et al. 2012). The difference to our findings may originate in different aspects. The clinical trials (Muller et al. 2006; Akhondzadeh et al. 2009; Abbasi et al. 2012) studied depressed patients, whereas this study investigated SSRI users, without specific knowledge of the indication. The increased risk for suicide attempts was only based on five individuals among celecoxib users. In this study, citalopram was used by 58% as compared to different antidepressants in the clinical studies. Furthermore, in this study, half of NSAID and paracetamol users were aged 70 years or older, whereas in the clinical trials, participants were mainly between 18 and 65 years of age. Thus, other psychiatric disorders may have contributed to the increased risk for psychiatric contacts observed in the current study.

Only one study reported that use of citalopram in combination with NSAIDs and paracetamol was associated with decreased antidepressant treatment effects (Warner‐Schmidt et al. 2011). The authors recommended a carefully balanced use of anti‐inflammatory agents in patients suffering from depression. Our results support a more differentiated view on this topic; NSAIDs are a very heterogeneous group of drugs (Knights et al. 2010) and both treatment effects and safety aspects varied across the different NSAIDs. Depression is often comorbid with painful conditions (Manning and Jackson 2013), why many require this combination therapy.

Side effects concerning use of SSRIs and NSAIDs has been intensively investigated (de Abajo and Garcia‐Rodriguez 2008; Schjerning Olsen et al. 2011). It is noteworthy, though that in this study, different NSAIDs showed different risk‐profiles and commonly used NSAIDs were not associated with important CVD or GI side effects. However, confounding by indication should always be kept in mind. Low‐dose ASA is used prophylactic, for example, among patients with a high risk for CVD adverse events, partly explaining the observed increased CVD risk. 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 2008). 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 (2.6 (95%‐CI: 1.4; 4.9)). This is in accordance with previous findings of limited increased risks among users of proton pump inhibitors (de Abajo and Garcia‐Rodriguez 2008).