Mortality associated with lithium and valproate treatment of US Veterans Health Administration patients with mental disorders.

BackgroundThe mood stabilisers lithium and valproate might plausibly have differing associations with mortality because of differing effects on mental health and various physiological indicators.AimsTo assess associations between lithium, valproate and non-suicide mortality.MethodIntention-to-treat, propensity score-matched cohort study.ResultsLithium was associated with significantly reduced non-suicide mortality in the intent-to-treat cohort over 0-90 days (hazard ratio (HR) = 0.67, 95% CI 0.51-0.87) but not longer. In secondary analyses, a sizeable reduction in mortality was observed during active treatment with lithium across all time periods studied (for example 365-day HR = 0.62, 95% CI 0.45-0.84), but significantly increased risks were observed among patients discontinuing lithium by 180 days (HR = 1.54, 95% CI 1.01-2.37).ConclusionsPatients initiating lithium had lower non-suicide mortality over 0-90 days than patients initiating valproate and consistently lower non-suicide mortality among patients maintaining treatment, but elevated risk among patients discontinuing treatment by 180 days. Although residual confounding or selection effects cannot be excluded, this study suggests potential benefits to enhancing lithium treatment persistence and the monitoring of patients discontinuing lithium. There is a need for further research.

Suicide risk in Veterans Health Administration patients with mental health diagnoses initiating lithium or valproate: a historical prospective cohort study.

BACKGROUND: Lithium has been reported in some, but not all, studies to be associated with reduced risks of suicide death or suicidal behavior. The objective of this nonrandomized cohort study was to examine whether lithium was associated with reduced risk of suicide death in comparison to the commonly-used alternative treatment, valproate. METHODS: A propensity score-matched cohort study was conducted of Veterans Health Administration patients (n=21,194/treatment) initiating lithium or valproate from 1999-2008. RESULTS: Matching produced lithium and valproate treatment groups that were highly similar in all 934 propensity score covariates, including indicators of recent suicidal behavior, but recent suicidal ideation was not able to be included. In the few individuals with recently diagnosed suicidal ideation, a significant imbalance existed with suicidal ideation more prevalent at baseline among individuals initiating lithium than valproate (odds ratio (OR) 1.30, 95% CI 1.09, 1.54; p=0.003). No significant differences in suicide death were observed over 0-365 days in A) the primary intent-to-treat analysis (lithium/valproate conditional odds ratio (cOR) 1.22, 95% CI 0.82, 1.81; p=0.32); B) during receipt of initial lithium or valproate treatment (cOR 0.86, 95% CI 0.46, 1.61; p=0.63); or C) after such treatment had been discontinued/modified (OR 1.51, 95% CI 0.91, 2.50; p=0.11). Significantly increased risks of suicide death were observed after the discontinuation/modification of lithium, compared to valproate, treatment over the first 180 days (OR 2.72, 95% CI 1.21, 6.11; p=0.015). CONCLUSIONS: In this somewhat distinct sample (a predominantly male Veteran sample with a broad range of psychiatric diagnoses), no significant differences in associations with suicide death were observed between lithium and valproate treatment over 365 days. The only significant difference was observed over 0-180 days: an increased risk of suicide death, among individuals discontinuing or modifying lithium, compared to valproate, treatment. This difference could reflect risks either related to lithium discontinuation or higher baseline risks among lithium recipients (i.e., confounding) that became more evident when treatment stopped. Our findings therefore support educating patients and providers about possible suicide-related risks of discontinuing lithium even shortly after treatment initiation, and the close monitoring of patients after lithium discontinuation, if feasible. If our findings include residual confounding biasing against lithium, however, as suggested by the differences observed in diagnosed suicidal ideation, then the degree of beneficial reduction in suicide death risk associated with active lithium treatment would be underestimated. Further research is urgently needed, given the lack of interventions against suicide and the uncertainties concerning the degree to which lithium may reduce suicide risk during active treatment, increase risk upon discontinuation, or both.

Patient and Treatment Characteristics Associated With Receipt of Core Patient-Reported Outcome Measures in VA Mental Health.

OBJECTIVE: Measurement-based care (MBC) has been implemented in Veterans Affairs since 2016 and is increasingly used in other mental health care organizations. Little quantitative research exists that assesses patient-level barriers and facilitators of MBC. This study examines correlates of receiving patient-reported outcome measures (PROMs) among veterans receiving both psychotherapy and pharmacotherapy (Both), psychotherapy only (Psychotherapy), and pharmacotherapy only (Pharmacotherapy). METHODS: Data on PROM administration were obtained for a 12-month period for 1,726,578 veterans who initiated outpatient mental health care during fiscal year 2019. Clinical, treatment, and PROM data were extracted from the electronic health record. Logistic regression was used to model the association between veteran and treatment characteristics and PROM administration. RESULTS: Thirty-two percent of veterans in Both, 26.0% in Psychotherapy, and 8.8% in Pharmacotherapy received at least one PROM. The probability of PROM administration was positively associated with the number of treatment encounters during the fiscal year 2019. Major depressive, generalized anxiety, and other depressive disorders were associated with an increased probability of PROM administration. Psychotic disorders, personality disorders, older age, dementia, and electronic health record suicide risk flag were associated with decreased odds of PROM administration across treatment types. CONCLUSIONS: Rates of PROM administration differ depending on the type of treatment received. The probability of PROM administration is influenced by the frequency of encounters and, to a lesser extent, having a diagnosis congruent with symptoms assessed in the set of PROMs considered. Consistent with hypotheses from the MBC implementation literature, potential indicators of clinical severity and cognitive impairment decrease the likelihood of PROM utilization.

Antidepressant agents and suicide death among US Department of Veterans Affairs patients in depression treatment.

BACKGROUND: Studies report mixed findings regarding antidepressant agents and suicide risks, and few examine suicide deaths. Studies using observational data can accrue the large sample sizes needed to examine suicide death, but selection biases must be addressed. We assessed associations between suicide death and treatment with the 7 most commonly used antidepressants in a national sample of Department of Veterans Affairs patients in depression treatment. Multiple analytic strategies were used to address potential selection biases. METHODS: We identified Department of Veterans Affairs patients with depression diagnoses and new antidepressant starts between April 1, 1999, and September 30, 2004 (N = 502,179). Conventional Cox regression models, Cox models with inverse probability of treatment weighting, propensity-stratified Cox models, marginal structural models (MSM), and instrumental variable analyses were used to examine relationships between suicide and exposure to bupropion, citalopram, fluoxetine, mirtazapine, paroxetine, sertraline, and venlafaxine. RESULTS: Crude suicide rates varied from 88 to 247 per 100,000 person-years across antidepressant agents. In multiple Cox models and MSMs, sertraline and fluoxetine had lower risks for suicide death than paroxetine. Bupropion had lower risks than several antidepressants in Cox models but not MSMs. Instrumental variable analyses did not find significant differences across antidepressants. DISCUSSION: Most antidepressants did not differ in their risk for suicide death. However, across several analytic approaches, although not instrumental variable analyses, fluoxetine and sertraline had lower risks of suicide death than paroxetine. These findings are congruent with the Food and Drug Administration meta-analysis of randomized controlled trials reporting lower risks for "suicidality" for sertraline and a trend toward lower risks with fluoxetine than for other antidepressants. Nevertheless, divergence in findings by analytic approach suggests caution when interpreting results.

Suicide among patients in the Veterans Affairs health system: rural-urban differences in rates, risks, and methods.

OBJECTIVES: Using national patient cohorts, we assessed rural-urban differences in suicide rates, risks, and methods in veterans. METHODS: We identified all Department of Veterans Affairs (VA) patients in fiscal years 2003 to 2004 (FY03-04) alive at the start of FY04 (n = 5,447,257) and all patients in FY06-07 alive at the start of FY07 (n = 5,709,077). Mortality (FY04-05 and FY07-08) was assessed from National Death Index searches. Census criteria defined rurality. We used proportional hazards regressions to calculate rural-urban differences in risks, controlling for age, gender, psychiatric diagnoses, VA mental health services accessibility, and regional administrative network. Suicide method was categorized as firearms, poisoning, strangulation, or other. RESULTS: Rural patients had higher suicide rates (38.8 vs 31.4/100,000 person-years in FY04-05; 39.6 vs 32.4/100,000 in FY07-08). Rural residence was associated with greater suicide risks (20% greater, FY04-05; 22% greater, FY07-08). Firearm deaths were more common in rural suicides (76.8% vs 61.5% in FY07-08). CONCLUSIONS: Rural residence is a suicide risk factor, even after controlling for mental health accessibility. Public health and health system suicide prevention should address risks in rural areas.

Suicide death over the first year of lithium versus valproate treatment in cohorts with and without bipolar disorder.

This study examined if lithium's association with suicide risk varies by diagnosis. We performed separate 1:1 high-dimensional propensity score (hdPS)-matching in US Veterans with and without bipolar disorder starting lithium or valproate. Among individuals with bipolar disorder, actively receiving lithium (compared to valproate) was not associated with suicide risk. However, in intent-to-treat analyses (following all individuals with bipolar disorder starting lithium or valproate for all 365 days, regardless of whether they stopped the medication), starting lithium was significantly associated with higher one-year risks of suicide (HR = 1.50, 95% CI: 1.05-2.15, p = 0.03). These intent-to-treat risks were attributable entirely to transiently elevated suicide risks observed among individuals no longer receiving lithium (significant at 180 days [HR = 6.10, CI: 1.37-27.3, p = 0.02] but not 365 days [HR = 2.05, CI: 0.88-4.79, p = 0.10]). Among individuals without bipolar disorder, depending on the analysis, actively receiving lithium was associated with nonsignificantly (HR = 0.43, CI: 0.15-1.20, p = 0.11) or significantly (HR = 0.28, CI: 0.08-0.98, p = 0.047) decreased one-year suicide risks. Study limitations included limited power, brief follow-up, and potential residual confounding. Residual confounding is suggested by the observation that more individuals diagnosed with suicidal ideation started lithium than valproate (with this difference being statistically significant for individuals with bipolar disorder, p = 0.0012). If it were possible to correct for this potential confounding, then the suicide-related risks associated with among individuals discontinuing lithium would be expected to be less, and the suicide-related benefits associated with actively receiving lithium (already statistically significant in some analyses among individuals without bipolar disorder) would be expected to increase. Further research is needed.

Higher-risk periods for suicide among VA patients receiving depression treatment: prioritizing suicide prevention efforts.

BACKGROUND: Health systems with limited resources may have the greatest impact on suicide if their prevention efforts target the highest-risk treatment groups during the highest-risk periods. To date, few health systems have carefully segmented their depression treatment populations by level of risk and prioritized prevention efforts on this basis. METHODS: We conducted a retrospective cohort study of 887,859 VA patients receiving depression treatment between 4/1/1999 and 9/30/2004. We calculated suicide rates for five sequential 12-week periods following treatment events that health systems could readily identify: psychiatric hospitalizations, new antidepressant starts (>6 months without fills), "other" antidepressant starts, and dose changes. Using piecewise exponential models, we examined whether rates differed across time-periods. We also examined whether suicide rates differed by age-group in these periods. RESULTS: Over all time-periods, the suicide rate was 114/100,000 person-years (95% CI; 108, 120). In the first 12-week periods, suicide rates were: 568/100,000 p-y (95% CI; 493, 651) following psychiatric hospitalizations; 210/100,000 p-y (95% CI; 187, 236) following new antidepressant starts; 193/100,000 p-y (95% CI; 167, 222) following other starts; and 154/100,000 p-y (95% CI; 133, 177) following dose changes. Suicide rates remained above the base rate for 48 weeks following hospital discharge and 12 weeks following antidepressant events. Adults aged 61-80 years were at highest risk in the first 12-week periods. CONCLUSIONS: To have the greatest impact on suicide, health systems should prioritize prevention efforts following psychiatric hospitalizations. If resources allow, closer monitoring may also be warranted in the first 12 weeks following antidepressant starts, across all age-groups.

The prevalence and predictors of mental health treatment services in a national sample of depressed veterans.

BACKGROUND: Few studies of acute depression care have examined the provision of psychotherapy or combined treatment in addition to medication management. This study examined acute phase depression treatment in the VA healthcare system, including measures of medication treatment (MT), psychotherapy (PT), and combined treatment (CT = MT plus PT). Both low level care (receipt of any MT, PT, or CT, but all below guideline levels) as well as guideline concordant care (GC MT, PT, and CT) were examined. METHODS: The sample included 41,412 patients with new depression diagnoses. Analyses examined the relationship between demographics and psychiatric comorbidities (eg, substance use disorders, post-traumatic stress disorder, depression with both substance use disorders and post-traumatic stress disorder) and receipt of each type of care (low level and guideline concordant MT, PT, and CT). RESULTS: The majority (75%) received at least some treatment, with 35% of the sample receiving guideline concordant care (particularly GC MT). Those with psychiatric comorbidities generally were more likely to receive GC care, older veterans were less likely to receive each type of care, and African Americans were less likely to receive GC MT but more likely to receive GC PT and GC CT than whites. CONCLUSIONS: Although it is difficult to benchmark, the VA overall seems similar or better than the private sector in providing guideline concordant acute phase treatment for its depressed patients. The majority of veterans received some acute phase depression treatment, but only a minority seem to receive guideline concordant care (particularly PT and CT).

Does consideration of Medicare use affect VA evaluations of treatment for new episodes of depression?

This report evaluates whether consideration of out-of-system use affects Veterans Affairs (VA) health system assessments of depression treatment. We measured effective medication management and optimal practitioner contacts among veterans whose VA data indicated a new episode of depression. Among 3,567 VA patients who were Medicare age-eligible, VA data indicated that 69% received recommended antidepressant coverage and 9% received recommended practitioner contacts. After including Medicare data, 295 patients (8%) no longer met inclusion criteria. Among the remainder, 3% received Medicare depression treatment and 0.5% were re-classified as having recommended contacts. Medicare use does not substantially supplement VA depression treatment.

Suicide mortality among individuals receiving treatment for depression in the Veterans Affairs health system: associations with patient and treatment setting characteristics.

OBJECTIVES: We sought to report clinical and demographic factors associated with suicide among depressed veterans in an attempt to determine what characteristics identified depressed veterans at high risk for suicide. METHODS: We used longitudinal, nationally representative data (1999-2004) to determine suicide rates among depressed veterans, estimating time until suicide using Cox proportional hazards regression models. RESULTS: Of 807694 veterans meeting study criteria, 1683 (0.21%) committed suicide during follow-up. Increased suicide risks were observed among male, younger, and non-Hispanic White patients. Veterans without service-connected disabilities, with inpatient psychiatric hospitalizations in the year prior to their qualifying depression diagnosis, with comorbid substance use, and living in the southern or western United States were also at higher risk. Posttraumatic stress disorder (PTSD) with comorbid depression was associated with lower suicide rates, and younger depressed veterans with PTSD had a higher suicide rate than did older depressed veterans with PTSD. CONCLUSIONS: Unlike the general population, older and younger veterans are more prone to suicide than are middle-aged veterans. Future research should examine the relationship between depression, PTSD, health service use, and suicide risks among veterans.

What happened to lithium? Antidepressant augmentation in clinical settings.

OBJECTIVE: Antidepressant augmentation is recommended when patients do not respond to antidepressant monotherapy. However, little is know about antidepressant augmentation in clinical settings and whether these practices reflect the research evidence. METHOD: The authors identified 244,859 patients in Veterans Administration mental health settings with a diagnosis of depression and an antidepressant prescription during fiscal year 2002. Patients with schizophrenia, dementia, or bipolar I disorder were excluded. The authors examined the prevalence and characteristics of antidepressant augmentation during the year, defined as receiving an antidepressant and an augmenting agent (lithium, second-generation antipsychotics, combinations of antidepressants, anticonvulsants, or "other") for >/=60 consecutive days in specified doses for those without other clinical indications. Mixed-effect models were used to examine predictors of augmentation. RESULTS: Some patients (22%) received an augmenting agent. The most commonly used agents were a second antidepressant (11%) and a second-generation antipsychotic (7%). Only 0.5% of the patients received lithium. Whites, younger patients, and those with a prior hospitalization were more likely to receive augmentation. African Americans were more likely to receive antipsychotic augmentation; whites were more likely to receive lithium. CONCLUSIONS: Antidepressant augmentation is common in clinical settings. Although lithium currently has the most research support, antipsychotic medications and a second antidepressant are the most widely used augmenting agents. Many augmenting agents are used across clinical and demographic groups. Research is needed on the relative effectiveness of these agents, along with efforts to promote the use of agents with the greatest level of research support.

Risk of smoking and receipt of cessation services among veterans with mental disorders.

OBJECTIVE: The purpose of this study was to determine rates of smoking and receipt of provider recommendations to quit smoking among patients with mental disorders treated in U.S. Department of Veterans Affairs (VA) treatment settings. METHODS: The authors conducted a secondary analysis of the yearly, cross-sectional 2007 Veterans Health Administration Outpatient Survey of Healthcare Experiences of Patients (N=224,193). Logistic regression was used to determine the independent association of mental health diagnosis and the dependent variables of smoking and receipt of provider recommendations to quit smoking. RESULTS: Patients with mental disorders had greater odds of smoking, compared with those without mental disorders (p<.05). Those with various mental disorders reported similar rates of receiving services (more than 60% to 80% reported receiving selected services), compared with those without these disorders, except that those with schizophrenia had more than 30% lower odds of receiving advice to quit smoking from their physicians (p<.05). Moreover, those who had co-occurring posttraumatic stress disorder or substance use disorders had significantly greater odds of reporting that they received advice to quit, recommendations for medications, and physician discussions of quitting methods, compared with those without these disorders (p<.05). Older patients, male patients, members of ethnic minority groups, those who were unmarried, those who were disabled or unemployed, and those living in rural areas had lower odds of receiving selected services (p<.05). CONCLUSIONS: The majority of patients with mental disorders served by the VA reported receiving cessation services, yet their smoking rates remained high, and selected groups were at risk for receiving fewer cessation services, suggesting the continued need to disseminate cessation services.

Who receives outpatient monitoring during high-risk depression treatment periods?

OBJECTIVES: To examine the intensity of monitoring received by important patient subgroups during high-risk periods (the 12 weeks after psychiatric hospitalization and after new antidepressant starts). DESIGN: Retrospective secondary analysis of data from the Veterans Affairs (VA) National Registry for Depression using patients aged 65 and older receiving depression treatment from 1999 to 2004. SETTING: VA healthcare system. PARTICIPANTS: VA patients in depression treatment between April 1, 1999, and September 30, 2004, who had psychiatric inpatient stays (n=73,137) or new antidepressant starts (n=421,536). MEASUREMENTS: The relationship between the number of outpatient visits for each group and patient characteristics in the 12-week period after psychiatric hospitalizations and antidepressant starts. RESULTS: The characteristic associated with significantly lower rates of monitoring for both high-risk treatment periods was aged 65 and older. White race and living in the south or northeast were also associated with significantly lower rates of monitoring after new antidepressant starts and inpatient stays, respectively. Substance abuse disorders were associated with greater monitoring after both types of depression events but did not seem to interact with other patient characteristics in determining levels of monitoring. CONCLUSION: VA patients who are older, white, and living in the south or northeast receive less-intensive monitoring during high-risk treatment periods for suicide. This is of concern, given that older patients appear to be at higher risk for suicide, particularly after inpatient stays, and may need particular attention during this time frame. Adapted interventions and proactive outreach may be needed that target this patient group.

Severe pain predicts greater likelihood of subsequent suicide.

Using data from the 1999 Large Health Survey of Veterans, Veterans Affairs' medical records, and the National Death Index (N = 260,254), the association between self-reported pain severity and suicide among veterans as examined, after accounting for demographic variables and psychiatric diagnoses. A Cox proportional hazards regression demonstrated that veterans with severe pain were more likely to die by suicide than patients experiencing none, mild, or moderate pain (HR: 1.33; 95% CI: 1.15, 1.54), after controlling for demographic and psychiatric characteristics. These results indicate that pain evaluations should be included in comprehensive suicide assessments and suicide prevention efforts.

Examining the relationship between clinical monitoring and suicide risk among patients with depression: matched case-control study and instrumental variable approaches.

OBJECTIVE: To assess the relationship between closer monitoring of depressed patients during high-risk treatment periods and death from suicide, using two analytic approaches. DATA SOURCE: VA patients receiving depression treatment between 1999 and 2004. STUDY DESIGN: First, a case-control design was used, adjusting for age, gender, and high-risk days (1,032 cases and 2,058 controls). Second, an instrumental variable (IV) approach (N=714,106) was used, with IVs of (1) average monitoring rates in the VA facility of most use and (2) monitoring rates of VA facilities weighted inversely by distance from patients' residences. PRINCIPAL FINDINGS: The case-control approach indicated a modest increase in suicide risk with each additional visit (odds ratio=1.02; 95 percent confidence interval=1.002, 1.04). The "facility used" IV estimate indicated near zero change in risk (0.0008 percent increase; p=.97) with each additional visit, while the distance-weighted IV estimate indicated a 0.032 percent decrease in risk (p=.29). An alternative analysis assuming a threshold effect of ≥4 visits during high-risk periods also showed a decrease (0.15 percent; p=.08) using the distance IV. CONCLUSIONS: The IV approach appeared to address the selection bias more appropriately than the case-control analysis. Neither analysis clearly indicated that closer monitoring during high-risk periods was significantly associated with reduced suicide risks, but the distance-weighted IV estimate suggested a potentially protective effect.

Service implications of providing intensive monitoring during high-risk periods for suicide among VA patients with depression.

OBJECTIVES: Department of Veterans Affairs (VA) patients in depression treatment have high suicide rates after psychiatric hospitalization, antidepressant starts, and dosage changes. Policy makers have recommended closer monitoring during these periods to reduce suicide. This study assessed the frequency of high-risk periods in clinical settings, the levels of monitoring provided during these periods, and the estimated costs of providing monitoring consistent with the most stringent Food and Drug Administration recommendation for treatment periods after antidepressant change (seven visits in the first 12 weeks). METHODS: Monitoring visits were identified in the 12-week period after antidepressant starts and dosage changes and after discharge from psychiatric hospitalization for 100,000 randomly selected VA patients in depression treatment between April 1, 1999, and September 30, 2004. Incremental costs of providing intensive monitoring were estimated by using VA Health Economics Resource Center average cost data. RESULTS: Patients averaged less than one high-risk period each year. They completed an average of 2.4 monitoring visits during the 12-week period after antidepressant treatment events and 4.9 visits after psychiatric hospitalization. Providing intensive monitoring would cost an additional $408-$537 for each high-risk period after antidepressant treatment events and $313-$341 for each high-risk period after psychiatric hospitalization. During fiscal year 2004 providing intensive monitoring during all high-risk periods would have cost an additional $183-$270 million. Providing intensive monitoring only after psychiatric hospitalizations would have cost an additional $15-$17 million. CONCLUSIONS: Providing intensive monitoring for VA patients in depression treatment during all high-risk periods for suicide would require substantial services reorganization and incremental expenditures. Modest expenditures would support intensive monitoring during the highest-risk period that follows psychiatric hospitalization.

Exploratory data mining analysis identifying subgroups of patients with depression who are at high risk for suicide.

OBJECTIVE: Although prior research has identified a number of separate risk factors for suicide among patients with depression, little is known about how these factors may interact to modify suicide risk. Using an empirically based decision tree analysis for a large national sample of Veterans Affairs (VA) health system patients treated for depression, we identified subgroups with particularly high or low rates of suicide. METHOD: We identified 887,859 VA patients treated for depression between April 1, 1999, and September 30, 2004. Randomly splitting the data into 2 samples (primary and replication samples), we developed a decision tree for the primary sample using recursive partitioning. We then tested whether the groups developed within the primary sample were associated with increased suicide risk in the replication sample. RESULTS: The exploratory data analysis produced a decision tree with subgroups of patients at differing levels of risk for suicide. These were identified by a combination of factors including a co-occurring substance use disorder diagnosis, male sex, African American race, and psychiatric hospitalization in the past year. The groups developed as part of the decision tree accurately discriminated between those with and without suicide in the replication sample. The patients at highest risk for suicide were those with a substance use disorder who were non-African American and had an inpatient psychiatric stay within the past 12 months. CONCLUSIONS: Study findings suggest that the identification of depressed patients at increased risk for suicide is improved through the examination of higher order interactions between potential risk factors.