Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A "cytokine hypothesis" of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, "sequenced treatment alternatives to relieve depression" (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.     

Cardiovascular effects of selective serotonin reuptake inhibitors and other novel antidepressants

This paper reviews the current knowledge of cardiovascular effects of the most commonly used novel antidepressants and their possible interactions with cardiovascular medications. The literature was reviewed through Medline 1980-2001. Materials were located by using terms such as SSRIs, individual names of novel antidepressants matched with terms like cardiovascular effects, cardiovascular diseases, cardiovascular risk factors, etc. Drug compendiums from 1998-2001 and some psychopharmacology texts were also used. The article focuses on the cardiovascular effects of the newer antidepressants, their use in patients with cardiovascular disease, and interactions with various commonly used cardiovascular drugs.     

Effect of selective serotonin reuptake inhibitors on the risk of fracture

BACKGROUND: Depression and osteoporotic fractures are common ailments among elderly persons. Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of depression in this population, and the association between daily SSRI use and fragility fractures is unclear. Our objective was to examine the effect of daily SSRI use on the risk of incident clinical fragility fracture. METHODS: A population-based, randomly selected, prospective cohort study of 5008 community-dwelling adults 50 years and older, followed up over 5 years for incident fractures. Clinical fragility fractures were classified as minimal trauma fractures that were clinically reported and radiographically confirmed. The risk of fragility fracture associated with daily SSRI use was determined while controlling for relevant covariates. RESULTS: Daily SSRI use was reported by 137 subjects. After adjustment for many potential covariates, daily SSRI use was associated with substantially increased risk of incident clinical fragility fracture (hazard rate, 2.1; 95% confidence interval, 1.3-3.4). Daily SSRI use was also associated with increased odds of falling (odds ratio, 2.2; 95% confidence interval, 1.4-3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose dependent and were similar for those who reported taking SSRIs at baseline and at 5 years' follow-up. CONCLUSIONS: Daily SSRI use in adults 50 years and older remained associated with a 2-fold increased risk of clinical fragility fracture after adjustment for potential covariates. Depression and fragility fractures are common in this age group, and the elevated risk attributed to daily SSRI use may have important public health consequences.     

Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks

The selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of multiple psychiatric conditions. In vitro and ex vivo data with these agents indicate they may have varying degrees of antiplatelet activity via multiple receptors. Reports of bleeding in patients receiving SSRIs appeared soon after their introduction. A review of the literature suggests SSRI therapy may increase the risk of bleeding especially with concomitant aspirin or nonsteroidal anti-inflammatory agents. Clinicians should exercise caution when prescribing these agents in high risk patients and maintain awareness of the potential contribution of SSRIs to unexplained bleeding episodes.     

Use of selective serotonin reuptake inhibitors and sleep disturbances in community-dwelling older women

OBJECTIVES: To determine the association between use of selective serotonin reuptake inhibitors (SSRIs) and objective measures of sleep disturbances in older community-dwelling women, including women without evidence of depression. DESIGN: Cross-sectional study. SETTING: Four U.S. clinical centers. PARTICIPANTS: Two thousand eight hundred fifty-three women aged 71 and older (2,630 nonusers of antidepressants and 223 taking SSRIs alone, not in combination with other antidepressants). MEASUREMENTS: Medication use, assessed using an interviewer-administered questionnaire with verification of use from medication containers and computerized dictionary used to categorize type of medication; evidence of depression assessed using self-report or a score of 6 or higher on the Geriatric Depression Scale; and sleep parameters measured using a wrist actigraph, with data collected for an average of four consecutive 24-hour periods. RESULTS: Of the overall cohort of 2,853 women and of 2,337 women without evidence of depression, sleep disturbances were more common in women taking SSRIs than in those not taking antidepressants. After excluding women with evidence of depression and adjusting for multiple potential confounders, women taking SSRIs were more likely to have a sleep duration of 5 hours or less (multivariate odds ratio (MOR)=2.15, 95% confidence interval (CI)=1.04-4.47), sleep efficiency less than 70% (MOR=2.37, 95% CI=1.32-4.25), sleep latency of 1 hour or more (MOR=3.99, 95% CI=2.29-6.96) and eight or more long wake episodes (MOR=1.75, 95% CI=0.99-3.10). CONCLUSION: SSRI use by older women, including those without evidence of depression, is associated with a greater likelihood of sleep disturbances, including poorer sleep efficiency, longer sleep latency, and sleep fragmentation, manifested by multiple long wake episodes. These results add to the uncertainty regarding risks and benefits of SSRI use in aged populations.     

Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting

Depression is increasingly recognized as an independent prognostic risk factor in patients with coronary artery disease and coronary artery bypass grafting (CABG). The use of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with cardiac disease is becoming more prevalent. We examined the long-term outcomes of patients on SSRIs before CABG. We prospectively examined collected data in the Duke Databank for Cardiovascular Disease from January 1, 1999 to December 31, 2003. The median and maximum follow-up periods were 3 and 6 years, respectively. We screened patients who underwent CABG (n = 5,364) and excluded those who underwent simultaneous CABG and valvular surgery (n = 570). SSRI antidepressants included fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, and clomipramine, and their use was determined from the inpatient pharmacy records during the index hospitalization. Outcomes included event-free survival from all-cause mortality, rehospitalization, and a composite end point of all-cause mortality or rehospitalization. Of 4,794 CABG-only patients, 246 (5.1%) took SSRIs before CABG. The SSRI group had a higher prevalence of diabetes, hypercholesterolemia, hypertension, cerebrovascular disease, peripheral vascular disease, and previous cardiovascular intervention. After adjustment for baseline differences, patients on SSRIs before CABG had increased risks of mortality, rehospitalization, and the composite end point (hazard ratio 1.61, 95% confidence interval 1.17 to 2.21, p = 0.003; hazard ratio 1.52, 95% confidence interval 1.30 to 1.77, p <0.0001; and hazard ratio 1.46, 95% confidence interval 1.26 to 1.70, p <0.0001, respectively). In conclusion, SSRI use before CABG was associated with a higher risk of long-term post-CABG mortality and rehospitalization. The explanation behind these findings requires further research.     

Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins

BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs. METHODS: We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs. RESULTS: We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as "nongastrointestinal bleeding") (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as "gastrointestinal bleeding") (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5). CONCLUSION: In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.     

选择性5-HT再摄取抑制剂与胃肠道损害的研究进展

选择性5-羟色胺再摄取抑制剂(SSRIs)是全世界最常见的处方药之一,目前临床上广泛用于抑郁症治疗,与三环类抗抑郁药(TCAs)药效相当,但比TCAs安全且耐受性好.然而,随着SSRIs使用人群的增加.一些病例报道和流行病学研究开始报道SSRJs治疗后出现胃肠道出血并发症.本文就SSRIs的临床应用与胃肠道出血的相关性...