Use of Nonsteroidal Anti-Inflammatory Drugs and Bladder Cancer Risk: A Meta-Analysis of Epidemiologic Studies

Purpose

Several epidemiologic studies have evaluated the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and bladder cancer risk and the results were varied. Thus, we conducted a comprehensive meta-analysis of studies exclusively dedicated to the relationship between the 3 most commonly used analgesics and bladder cancer risk.

Methods

A systematic literature search up to November 2012 was performed in PubMed database for 3 categories of analgesics: acetaminophen, aspirin or non-aspirin NSAIDs. Study-specific risk estimates were pooled using a random-effects model.

Results

Seventeen studies (8 cohort and 9 case-control studies), involving a total of 10,618 bladder cancer cases, were contributed to the analysis. We found that acetaminophen (relative risk [RR] 1.01, 95% confidence interval [CI] 0.88–1.17) and aspirin (RR 1.02, 95% CI 0.91–1.14) were not associated with bladder cancer risk. Although non-aspirin NSAIDs was statistically significantly associated with reduced risk of bladder cancer among case-control studies (but not cohort studies), the overall risk was not statistically significant (RR 0.87, 95% CI 0.73–1.05). Furthermore, we also found that non-aspirin NSAIDs use was significantly associated with a 43% reduction in bladder cancer risk among nonsmokers (RR 0.57, 95% CI 0.43–0.76), but not among current smokers.

Conclusion

The results of our meta-analysis suggest that there is no association between use of acetaminophen, aspirin or non-aspirin NSAIDs and bladder cancer risk. However, non-aspirin NSAIDs use might be associated with a reduction in risk of bladder cancer for nonsmokers.     

Tea consumption and risk of bladder cancer: a meta-analysis

ABSTRACT: BACKGROUND: Tea consumption has been reported to be associated with an decreased risk of several types of cancers. However, the results based on epidemiological studies on the association of tea consumption with bladder cancer were inconsistent. This meta-analysis was undertaken to evaluate the relationship between tea consumption and bladder cancer risk. METHODS: Eligible studies were retrieved via both computer searches and review of references. The summary relative risk (RR) with 95% confidence interval (CI) was calculated. RESULTS: Twenty three studies met the inclusion criteria of the meta-analysis. No association with bladder cancer was observed in either overall tea consumption group (OR =0.94, 95% CI 0.85-1.04) or subgroups stratified by sex, study design, geographical region or tea types. CONCLUSIONS: Our findings did not support that tea consumption was related to the decreased risk of bladder cancer.     

Mortality among oral contraceptive users: 20 year follow up of women in a cohort study.

OBJECTIVE--To see whether the use of oral contraceptives influences mortality. DESIGN--Non-randomised cohort study of 17,032 women followed up on an annual basis for an average of nearly 16 years. SETTING--17 Family planning clinics in England and Scotland. SUBJECTS--Women recruited during 1968-74. At the time of recruitment each woman was aged 25-39, married, a white British subject, willing to participate, and either a current user of oral contraceptives or a current user of a diaphragm or intrauterine device (without previous exposure to the pill). MAIN OUTCOME MEASURES--Overall mortality and cause specific mortality. RESULTS--238 Deaths occurred during the follow up period. The main analyses concerned women entering the study while using either oral contraceptives or a diaphragm or intrauterine device. The overall relative risk of death in the oral contraceptive users was 0.9 (95% confidence interval 0.7 to 1.2). Though the numbers of deaths were small in most individual disease categories, the trends observed were generally consistent with findings in other reports. Thus the relative risk of death in the oral contraceptive users was 4.9 (95% confidence interval 0.7 to 230) for cancer of the cervix, 3.3 (95% confidence interval 0.9 to 17.9) for ischaemic heart disease, and 0.4 (95% confidence interval 0.1 to 1.2) for ovarian cancer. There was a linear trend in the death rates from cervical cancer and ovarian cancer (in opposite directions) with total duration of oral contraceptive use. Death rates from breast cancer (relative risk 0.9; 95% confidence interval 0.5 to 1.4) and suicide and probable suicide (relative risk 1.1; 95% confidence interval 0.3 to 3.6) were much the same in the two contraceptive groups. In 1981 the relative risk of death in oral contraceptive users from circulatory diseases as a group was reported to be 4.2 (95% confidence interval 2.3 to 7.7) in the Royal College of General Practitioners oral contraception study. The corresponding relative risk in this study was only 1.5 (95% confidence interval 0.7 to 3.0). CONCLUSIONS--These findings contain no significant evidence of any overall effect of oral contraceptive use on mortality. None the less, only small numbers of deaths occurred during the study period and a significant adverse (or beneficial) overall effect might emerge in the future. Interestingly, the mortality from circulatory disease associated with oral contraceptive use was substantially less than that found in the Royal College of General Practitioners study.     

An association between NQO1 genetic polymorphism and risk of bladder cancer

NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that plays a critical role in protecting cells against chemically induced oxidative stress, cytotoxicity, mutagenicity, and carcinogenicity. NQO1 protects cells from oxidative damage by preventing the generation of reactive oxygen species and reducing certain environmental carcinogens, such as nitroaromatic compounds, heterocyclic amines, and possible cigarette smoke condensate. A C-->T single nucleotide polymorphism in exon 6 was shown to reduce NQO1 enzyme activity, which may diminish the protection provided by NQO1. Therefore, we hypothesized that people with the variant allele genotypes of NQO1 are at higher risk for bladder cancer. In an ongoing case-control study, the NQO1 genotypes were successfully identified by polymerase chain reaction restriction fragment length polymorphism in 265 bladder cancer patients and 261 control subjects matched for age, sex, and ethnicity. The frequency of the variant NQO1 allele was 18% for controls and 21% for cases. The variant allele genotypes of NQO1 were associated with a higher risk of bladder cancer in Caucasians (odds ratio (OR)=1.51; 95% confidence interval (CI)=1.01-2.25). Further analysis in Caucasians showed an elevated bladder cancer risk in men (OR=1.75; 95% CI=1.08-2.85) but not in women (OR=1.16; 95% CI=0.57-2.37). In addition, the variant allele genotypes were associated with higher bladder cancer risk in ever smokers (OR=1.78; 95% CI=1.06-3.00), but not in never smokers (OR=1.19; 95% CI=0.65-2.20). These results suggest that the NQO1 genetic polymorphism modulates bladder cancer risk, especially in men and ever smokers.     

Genetic polymorphisms of glutathione S-transferase M1 and bladder cancer risk: a meta-analysis of 26 studies

Studies investigating the association between glutathione S-transferase M1 (GSTM1) polymorphism and bladder cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. We performed a systematic search of the National Library of Medline and Embase databases. This meta-analysis included 26 case-control studies, which included 5029 bladder cancer cases and 6680 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of bladder cancer (OR = 1.46, 95% confidence interval [CI] = 1.35, 1.57). When stratifying for race, results were similar among Asians (OR = 1.60, 95% CI = 1.27, 2.01) and Caucasians (OR = 1.44, 95% CI = 1.33, 1.57) except Africans (OR = 1.25, 95% CI = 0.76, 2.06). When stratifying by the smoking, stage, grade, and histological type of bladder cancer, we found no statistical association. Our meta-analysis suggests that the GSTM1 null genotype is associated with a modest increase in the risk of bladder cancer.     

Family history of cancer and the risk of bladder cancer: A case–control study from Italy

BackgroundA family history of bladder cancer has been associated with the risk of bladder cancer, but quantification of the excess risk in different populations is still a relevant issue. Further, the role of a family history of other cancers on the risk of bladder cancer remains unclear.MethodsWe analyzed data from an Italian case–control study, including 690 bladder cancer cases and 665 hospital controls. Odds ratios (ORs) were estimated through unconditional logistic regression models, adjusted for sex, age, study center, year of interview and further for education, smoking and sibling’s number.ResultsThe OR for family history of bladder cancer was 2.13 (95% confidence intervals (95%CIs) 1.02–4.49) from the model with partial adjustment, and 1.99 (95%CI 0.91–4.32) after additional adjustment for smoking and siblings’ number, based on 23 cases (3.3%) and 11 controls (1.7%) with a family history of bladder cancer. The fully adjusted OR was 3.77 when the relative was diagnosed at age below 65 years. Smokers with a family history of bladder cancer had a four-fold increased risk compared to non-smokers without a family history. Bladder cancer risk was significantly increased among subjects with a family history of hemolymphopoietic cancers (OR = 2.97, 95%CI 1.35–6.55). Family history of cancer at other sites showed no significant association with bladder cancer risk.ConclusionThis study confirms an approximately two-fold increased risk of bladder cancer for family history of bladder cancer, and indicates a possible familial clustering of bladder cancer with cancers of the hemolymphopoietic system.     

Susceptibility of XPD and RAD51 genetic variants to carcinoma of urinary bladder in North Indian population

For the present study, two polymorphisms, xeroderma pigmentosum, complementation group D (XPD) Lys751Gln and RAD51 135G/C were studied with regard to bladder cancer. For XPD Lys751Gln polymorphism, an increased risk of bladder cancer was found to be associated with the Gln variant allele (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.27-2.73), on taking AA (Lys/Lys) as the referent genotype. In males, the XPD 751C (Gln) allele was found to be associated with a significantly increased risk (OR=2.33, 95% CI=1.52-3.56). The inhabitants of rural areas showed a significantly increased risk with the XPD Gln allele (OR=2.59, 95% CI=1.46-4.62) when compared with those of urban areas. In smokers (OR=5.30, 95% CI=2.42-11.68), alcohol drinkers (OR=4.33, 95% CI=2.17-8.70), and nonvegetarians (OR=2.21, 95% CI=1.26-3.87), the XPD Gln allele showed a significantly increased risk toward bladder cancer. For RAD51 135G/C polymorphism, no significant difference was observed in the allelic and genotypic frequencies. Even after stratification, no significant association could be seen. After stratifying histopathologically, the RAD51 CC genotype was associted with decreased risk in subjects having superficial stage (OR=0.51, 95% CI=0.27-0.99) and with those having G2 grade (OR=0.24, 95% CI=0.09-0.62) of bladder cancer. XPD polymorphism may be a predisposing factor, but the same cannot be said for RAD51 gene polymorphism.     

Breast implants and cancer: causation, delayed detection, and survival

Concern for many women with breast implants has been focused on three topics: cancer (both breast and other cancers), delayed detection of breast cancer, and increased breast cancer recurrence or decreased length of survival. In this study, a qualitative review of the literature on these subjects was conducted, coupled with a meta-analysis of the risk for breast cancer or other cancers (excluding that of the breast). Researchers have consistently found no persuasive evidence of a causal association between breast implants and any type of cancer. The meta-analysis results obtained by combining the epidemiology studies support the overall conclusion that breast implants do not pose any additional risk for breast cancer (relative risk, 0.72; 95% confidence interval, 0.61 to 0.85) or for other cancers (relative risk, 1.03; 95% confidence interval, 0.87 to 1.24). This analysis suggests that breast implants may confer a protective effect against breast cancer. Women with implants should be reassured by the consistency of scientific studies which have uniformly determined that, compared with women without implants, they are not at increased risk for cancer, are not diagnosed with later-stage breast malignancies, are not at increased risk for breast cancer recurrence, and do not have a decreased length of survival.     

Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased?

OBJECTIVE--To quantify the effect of selection of relatively healthy women in studies reporting reduced relative risk for cardiovascular disease in postmenopausal women taking hormone replacement therapy. DESIGN--Review of the follow up studies reported in three recent meta-analyses to determine the effect of oestrogen therapy on both total cancer and cardiovascular disease. The same standard statistical methods as in the original analyses were used. MAIN OUTCOME MEASURES--Relative risks of total cancer and cardiovascular disease. RESULTS--In most of the follow up studies the relative risk for total cancer was below 1. The studies that showed the largest reduction in cardiovascular disease also showed the largest reduction in cancer, indicating a healthy cohort effect. Although heterogeneity within the studies prevented pooling, the best estimate for the protective effect on total cancer was a relative risk of 0.83 among women taking oestrogen (95% confidence interval 0.71 to 0.96), while in the same studies the relative risk for cardiovascular disease was 0.57 (0.50 to 0.64). CONCLUSIONS--Unintended selection of relatively healthy women for oestrogen therapy may have influenced the reported beneficial effect of oestrogen therapy on cardiovascular disease. It is unclear how much of the cardioprotection is due to this selection. Universal preventive hormonal replacement therapy for postmenopausal women is unwarranted at present.     

Astrocytoma risk related to job exposure to electric and magnetic fields

To investigate the association between occupational exposure to low-frequency electric and magnetic (EM) fields and risk of brain tumors, a study was performed in Los Angeles County on 272 male adults with primary intracranial gliomas or meningiomas and 272 neighborhood controls. Complete occupational histories were collected. Risk associated with employment for more than 10 years in jobs that are presumed to entail exposure to EM fields was computed for various histological groupings. A nonsignificantly elevated risk of 1.7 was found for gliomas (all types pooled: 95% confidence interval 0.7-4.4), and a nonsignificantly reduced risk of 0.3 (95% confidence interval 0.03-3.2) was found for meningiomas. For astrocytomas, which form a subtype of the gliomas, a significantly elevated risk of 10.3 (95% confidence interval 1.3-80.8) was found; a significant upward trend (P = .01) of tumor incidence with increasing length of employment was observed. Most astrocytoma patients who worked in occupations involving exposure to EM fields were electricians or electrical engineers.     

Loss of employment and mortality.

OBJECTIVE--To assess effect of unemployment and early retirement on mortality in a group of middle aged British men. DESIGN--Prospective cohort study (British Regional Heart Study). Five years after initial screening, information on employment experience was obtained with a postal questionnaire. SETTING--One general practice in each of 24 towns in Britain. SUBJECTS--6191 men aged 40-59 who had been continuously employed for at least five years before initial screening in 1978-80: 1779 experienced some unemployment or retired during the five years after screening, and 4412 remained continuously employed. MAIN OUTCOME MEASURE--Mortality during 5.5 years after postal questionnaire. RESULTS--Men who experienced unemployment in the five years after initial screening were twice as likely to die during the following 5.5 years as men who remained continuously employed (relative risk 2.13 (95% confidence interval 1.71 to 2.65). After adjustment for socioeconomic variables (town and social class), health related behaviour (smoking, alcohol consumption, and body weight), and health indicators (recall of doctor diagnoses) that had been assessed at initial screening the relative risk was slightly reduced, to 1.95 (1.57 to 2.43). Even men who retired early for reasons other than illness and who appeared to be relatively advantaged and healthy had a significantly increased risk of mortality compared with men who remained continuously employed (relative risk 1.87 (1.35 to 2.60)). The increased risk of mortality from cancer was similar to that of mortality from cardiovascular disease (adjusted relative risk 2.07 and 2.13 respectively). CONCLUSIONS--In this group of stably employed middle aged men loss of employment was associated with an increased risk of mortality even after adjustment for background variables, suggesting a causal effect. The effect was non-specific, however, with the increased mortality involving both cancer and cardiovascular disease.     

Quantitative assessment of the association between TP53 Arg72Pro polymorphism and bladder cancer risk

Previous studies investigating the association between TP53 Arg72Pro polymorphism and bladder cancer risk reported controversial results. To quantify the strength of association between TP53 Arg72Pro polymorphism and bladder cancer risk, we performed this meta-analysis. We searched PubMed, Embase and Wangfang databases for studies relating the association between TP53 Arg72Pro polymorphism and bladder cancer risk. We used the pooled odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) to assess the association. Finally, data were available from a total of 16 case–control studies including a total of 5, 545 subjects (2,345 cases and 3,200 controls). Meta-analysis of all 16 studies showed TP53 Arg72Pro polymorphism was not associated with bladder cancer risk (All P values were more than 0.10). Subgroup analyses by ethnicity showed that TP53 Arg72Pro polymorphism contributed to bladder cancer risk in East Asians in three genetic models (For Pro vs. Arg, Fixed-effects OR 1.18, 95 % CI 1.05–1.32; For ProPro vs. ArgArg, Fixed-effects OR 1.40, 95 % CI 1.11–1.77; For ProPro vs. ArgPro/ArgArg, Fixed-effects OR 1.32, 95 % CI 1.07–1.62). However, there was no significant association in Caucasians and the others (All P values were more than 0.05). Heterogeneity analyses suggested ethnicity was the major sources of heterogeneity. Thus, meta-analyses of available data suggest the Pro variant of TP53 Arg72Pro contributes to bladder cancer risk in East Asians. Besides, TP53 Arg72Pro polymorphism may have race-specific effects on bladder cancer risk and further studies are needed to elucidate this possible effect.     

Urinary cell-free DNA as a potential tumor marker for bladder cancer

The objective was to assess the possibility of measuring urine creatinine (UCr)-adjusted urinary cell-free (ucf) DNA concentration as a noninvasive screening tool for bladder cancer. Using PicoGreen-based detection, the ucf-DNA/UCr concentration was quantified in urine supernatant specimens from 46 bladder cancer patients and 98 controls and compared to 400-bp real-time PCR-based detection, which detected the amplification of 400-bp beta-actin (named 400-bp ucf-DNA/UCr). The mean concentrations for both PicoGreen and 400-bp ucf-DNA (ng/mL)/UCr (mg/dL) were significantly higher in bladder cancer patients than in controls: 15.28 vs 6.68 (p<0.001, t-test) and 14.98 vs 1.07 (p<0.001), respectively. Among different stages and grades, no significant difference was found between these two methods. The areas under the ROC curves of PicoGreen and 400-bp ucf-DNA/UCr were 0.571 (95% confidence interval, 0.451-0.692) and 0.805 (95% confidence interval, 0.713-0.896), respectively. In 400-bp ucf-DNA/UCr, the best sensitivity and specificity were 86.1% and 72.0% at the cutoff value of 0.0645. These data indicated that 400-bp ucf-DNA/UCr is more reliable for bladder cancer detection than PicoGreen. In conclusion, our results suggest that ucf-DNA/UCr can be used as a potential tumor marker for bladder cancer, especially for detecting longer DNA fragments.     

Food consumption,meat cooking methods and diet diversity and the risk of bladder cancer

BackgroundSince food metabolites are eliminated by the urinary tract, several studies have investigated the association between diet and bladder cancer risk. Recently, the World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) suggested a potential beneficial effect of some foods (mainly vegetables, fruit, and milk) in the development of bladder cancer. We investigated the association between food groups and bladder cancer risk, seeking insights into food diversity as well as meat cooking methods.MethodsData were derived from an Italian multicentre case–control study, conducted between 2003 and 2014, including 690 bladder cancer cases and 665 frequency-matched controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) for various dietary aspects were estimated by unconditional logistic regression models adjusted for energy intake and the major known risk factors for bladder cancer.ResultsComparing the highest versus the lowest quartiles, consumption of vegetables (OR = 0.62; 95%CI: 0.44-0.88) and milk/yogurt (OR = 0.62; 95%CI: 0.44–0.87) reduced the risk of bladder cancer. Conversely, consumption of meat increased bladder cancer risk with an OR of 1.57 (95%CI: 1.07–2.31), particularly when the meat was stewed (OR = 1.47; 95%CI: 1.03–2.09) or roasted (OR = 1.41; 95%CI: 1.00–1.99). There was a suggestion that a diversified diet reduced the risk of bladder cancer, but this was not significant.ConclusionsOur study consolidates the role of diet in bladder cancer aetiology, showing a reduced risk for vegetable and milk/yogurt consumption and an increased risk for meat consumption, especially when the meat is stewed or roasted.     

Genomic conservation of cattle microsatellite loci in wild gaur (Bos gaurus) and current genetic status of this species in Vietnam

Background

Cigarette smoking and chemical occupational exposure are the main known risk factors for bladder transitional cell carcinoma (TCC). Oxidative DNA damage induced by carcinogens present in these exposures requires accurate base excision repair (BER). The XRCC1 protein plays a crucial role in BER by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, we conducted a comprehensive analysis of 14 XRCC1 polymorphisms in a case-control study involving more than 1100 subjects.

Results

We found no evidence of an association between any of the 14 XRCC1 polymorphisms and bladder cancer risk. However, we found carriage of the variant Arg280His allele to be marginally associated with increased bladder cancer risk compared to the wild-type genotype (adjusted odds ratio [95% confidence interval], 1.50 [0.98–2.28], p = 0.06). The association was stronger for current smokers such that individuals carrying the variant 280His allele had a two to three-fold increased risk of bladder cancer compared to those carrying the wildtype genotype (p = 0.09). However, the evidence for gene-environment interaction was not statistically significant (p = 0.45).

Conclusion

We provide no evidence of an association between polymorphisms in XRCC1 and bladder cancer risk, although our study had only limited power to detect the association for low frequency variants, such as Arg280His.     

Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer.

OBJECTIVE--To determine whether use of the injectable contraceptive depot medroxyprogesterone acetate (Depo-Provera) affects the risk of breast cancer in women. DESIGN--A population based case-control study. SETTING--Nationwide community study. SUBJECTS--891 Women aged 25-54 with newly diagnosed breast cancer were compared with 1864 women selected at random from the electoral rolls. INTERVENTION--Women were interviewed by telephone about past use of contraceptives and about possible risk factors for breast cancer. MAIN OUTCOME MEASURE--Relative risk of breast cancer in women who had used medroxyprogesterone. RESULTS--Medroxyprogesterone had been used by 110 patients and 252 controls. Overall, the relative risk of breast cancer associated with any duration of use was 1.0 (95% confidence interval 0.80 to 1.3). In women aged 25-34 the relative risk was 2.0 (1.0 to 3.8). The relative risk was highest in women aged 25-34 who had used the drug for six years or longer, although there were few women in this category. Women who had used it for two years or longer before age 25 had an increased risk of breast cancer (relative risk 4.6; 1.4 to 15.1). CONCLUSION--Despite the lack of an overall association these findings suggest that medroxyprogesterone may increase the risk of breast cancer in young women.     

Variation in cancer risks, by mutation position, in BRCA2 mutation carriers

Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.     

Mortality and Suicide Risk in Treatment-Resistant Depression: An Observational Study of the Long-Term Impact of Intervention

Major depressive disorder is a common global disease that causes a significant societal burden. Most interventional studies of depression provide a limited assessment of the interventions on mortality and suicide risks. This study utilizes data from an observational registry of patients with major depressive disorder to determine the impact of intervention (vagus nerve stimulation or standard pharmacological/non-pharmacological therapy) and a latent factor, patient trajectory toward response, on mortality, suicide and suicidal ideation. A total of 636 patients were available for an intent-to-treat analysis of all-cause mortality, suicide and suicidal ideation. Patients treated with vagus nerve stimulation in addition to standard therapies experienced lower, but not statistically significant, all-cause mortality (vagus nerve stimulation 4.93 per 1,000 person-years vs. 10.02 per 1,000 patient years for treatment as usual) and suicide rates (vagus nerve stimulation 0.88 per 1,000 person-years vs. 1.61 per 1,000 patient years for treatment as usual). Treatment with vagus nerve stimulation produced a statistically lower relative risk of suicidal ideation 0.80, 95% confidence interval (0.68,0.95). Further, patients that responded to either treatment saw a 51% reduction in relative risk of suicidal behavior; relative risk and 95% confidence interval of 0.49 (0.41,0.58). In summary, we find that treatment with adjunctive vagus nerve stimulation can potentially lower the risk of all-cause mortality, suicide and suicide attempts.