Eric G. Smith

Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. METHOD Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ≥ 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. RESULTS 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (β = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. CONCLUSIONS This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00344682.

Predictors of Suicide in Patient Charts Among Patients With Depression in the Veterans Health Administration Health System: Importance of Prescription Drug and Alcohol Abuse

OBJECTIVE To identify factors recorded in electronic medical chart progress notes associated with suicide among patients who had received treatment for depression. METHOD The retrospective study sample consisted of 324 randomly selected US Veterans Health Administration (VHA) patients treated for depression who died by suicide from April 1, 1999, to September 30, 2004, stratified by geographic region, gender, and year of depression cohort entry and 312 control patients with depression who were alive on the date of suicide death (index date) and were from the same stratum as the matched suicide patient. In addition to constructing variables from administrative data, variables were abstracted from electronic medical chart notes in the year prior to the index date in 5 categories: clinical symptoms and diagnoses, substance use, life stressors, behavioral/ideation measures (eg, suicide attempts), and treatments received. Logistic regression was used to assess the associations. RESULTS Even after we adjusted for administratively available data, suicidal behaviors and substance-related variables were the strongest independent predictors of suicide. Prescription drug misuse had an odds ratio (OR) of 6.8 (95% CI, 2.5-18.5); history of suicide attempts, 6.6 (95% CI, 1.7-26.4); and alcohol abuse/dependence, 3.3 (95% CI, 1.9-5.7). Difficulty with access to health care was a predictor of suicide (OR = 2.9; 95% CI, 1.3-6.3). Receipt of VHA substance abuse treatment was protective (OR = 0.4; 95% CI, 0.1-0.9). CONCLUSIONS Prescription drug and alcohol misuse assessments should be prioritized in suicide assessments among depressed patients. Additionally, behavioral measures noted in electronic chart records may be useful in health system monitoring and surveillance and can potentially be accessed using word search or natural language processing approaches.

Suicide risk assessment received prior to suicide death by Veterans health administration patients with a history of depression

OBJECTIVE To examine the quality of suicide risk assessment provided to veterans with a history of depression who died by suicide between 1999 and 2004. METHOD We conducted a case-control study of suicide risk assessment information recorded in 488 medical charts of veterans previously diagnosed with major depression, depression not otherwise specified, dysthymia, or other, less common ICD-9-CM depression codes. Patients dying by suicide from April 1999 through September 2004 or comparison patients (n = 244 pairs) were matched for age, sex, entry year, and region. RESULTS Seventy-four percent of patients with a history of depression received a documented assessment of suicidal ideation within the past year, and 59% received more than 1 assessment. However, 70% of those who died of suicide did not have a documented assessment for suicidal ideation at their final Veterans Health Administration (VHA) visit, even if that visit occurred within 0 through 7 days prior to suicide death. Most patients dying by suicide denied suicidal ideation when assessed (85%; 95% CI, 75%-92%), even just 0 through 7 days prior to suicide death (73%; 95% CI, 39%-94%). Suicidal ideation was assessed more frequently during outpatient final visits with mental health providers (60%) than during outpatient final visits with primary care (13%) or other non-mental health providers (10%, P < .0001). CONCLUSIONS Most VHA patients with a history of depression received some suicide risk assessment within the past year, but suicide risk assessments were infrequently administered at the final visit of patients who eventually died by suicide. Among patients who had assessments, denial of suicidal ideation appeared to be of limited value. Practice changes are needed to improve suicide risk assessment among patients with histories of depression, including the development of assessment and prevention strategies that are less dependent on the presence or disclosure of suicidal ideation at scheduled medical visits.

Correlates of suicidality among patients with psychotic depression

The independent association of age and other factors with suicidality in patients with major depression with psychotic features was examined. Of the 183 study participants, 21% had a suicide attempt during the current episode. Male gender, Hispanic background, past suicide attempt, higher depression scores, and higher cognitive scores were each independently associated with greater intensity of current suicidality. Older age was independently associated with a lower risk of a lifetime suicide attempt. These findings reinforce the evidence that patients with psychotic depression are at high risk for suicide and underscore the importance of examining correlates of suicidality specific to patients with psychotic depression.

Association between antidepressant half-life and the risk of suicidal ideation or behavior among children and adolescents: confirmatory analysis and research implications

BACKGROUND This study sought to determine from a recent meta-analysis of pediatric antidepressant trials if a general property of antidepressant medications--the multiple-dosing medication half-life--is associated with risks for suicidal ideation or behavior. METHODS Relative risks for suicidal behavior (ideation, attempt, or preparation) for seven antidepressants were obtained from both the FDAs initial and published versions of their pediatric antidepressant meta-analysis. The correlation between the relative risk for suicidal behavior and antidepressant half-life was examined using a nonparametric test, Spearmans rho. RESULTS A significant correlation (rho=0.929; p=0.003) was observed for the initial analysis, as previously reported by Weiss and Gorman. The correlation was robust to a change in the suicidality ranking for the longest half-life medication, fluoxetine, that occurred when results from the Treatment of Adolescent Depression Study (TADS) were included in the published meta-analysis (rho=0.786, p=0.036). LIMITATIONS In addition to limitations common to meta-analyses, our analysis has additional uncertainties including the fact that adult, rather than pediatric, antidepressant half-life data were used due to an unavailability of published information. In addition, risks for suicidal ideation/behavior may vary for reasons other than half-life (e.g. study eligibility criteria, illness severity or responsiveness to treatment, diagnoses, etc.). CONCLUSIONS The risk of suicidal ideation or behavior in short-term antidepressant trials involving children or adolescents, as defined in the recent FDA meta-analysis, appears to be potentially at least partly associated with antidepressant half-life. Although any relationship is tentative, approaches to investigating several potential candidate mechanisms for any association are discussed.

Treatment of Veterans with depression who died by suicide: timing and quality of care at last Veterans Health Administration visit

OBJECTIVE To examine the recency and quality of the last Veterans Health Administration (VHA) visit for patients with depression who died by suicide. METHOD We obtained services and pharmacy data for all 1,843 VHA patients with diagnosed depressive disorders (DSM-IV criteria) who died by suicide from April 1999 through September 2004. We ascertained the location and timing of their final VHA visit. For visits occurring within 30 days of suicide, we examined 3 quality indicators: (1) evidence that mental illness was a focus of the final visit, (2) adequacy of antidepressant dosage, and (3) recent receipt of mental health services. RESULTS Just over half of the patients (51%) with depression diagnoses had a VHA visit within 30 days of suicide. A minority of these patients (43%) died by suicide within 30 days of a final visit with mental health services, although 64% had received such services within 91 days of their suicide. Among the 57% of patients who died by suicide within 30 days and who were seen in non-mental health settings for their final visit, only 34% had a mental health condition coded at the final visit, and only 41% were receiving adequate dosages of antidepressant (versus 55% for those last seen by mental health services) (P < .0005). CONCLUSIONS Veterans Health Administration patients with depression who died by suicide within 30 days of their final visit received relatively high rates of mental health services, but most final visits still occurred in non-mental health settings. Increased referrals to mental health services, attention to mental health issues in non-mental health settings, and focus on antidepressant treatment adequacy by all providers might have reduced suicide risks for these patients.

Association between consistent purchase of anticonvulsants or lithium and suicide risk: a longitudinal cohort study from Denmark, 1995-2001

BACKGROUND Prior studies suggest anticonvulsants purchasers may be at greater risk of suicide than lithium purchasers. METHODS Longitudinal, retrospective cohort study of all individuals in Denmark purchasing anticonvulsants (valproic acid, carbamazepine, oxcarbazepine or lamotrigine) (n=9952) or lithium (n=6693) from 1995-2001 who also purchased antipsychotics at least once (to select out nonpsychiatric anticonvulsant use). Poisson regression of suicides by medication purchased (anticonvulsants or lithium) was conducted, controlling for age, sex, and calendar year. Confounding by indication was addressed by restricting the comparison to individuals prescribed the same medication: individuals with minimal medication exposure (e.g., who purchased only a single prescription of anticonvulsants) were compared to those individuals with more consistent medication exposure (i.e., purchasing > or = 6 prescriptions of anticonvulsants). RESULTS Demographics and frequency of anticonvulsant, lithium, or antipsychotic use were similar between lithium and anticonvulsant purchasers. Among patients who also purchased antipsychotic at least once during the study period, purchasing anticonvulsants more consistently (> or = 6 prescriptions) was associated with a substantial reduction in the risk of suicide (RR=0.22, 95% CI=0.11-0.42, p<0.0001), similar to patients consistently purchasing lithium (RR=0.27, 95% CI=0.12-0.62, p=0.006). Absolute suicide risks of consistent anticonvulsant and consistent lithium purchasers were similar. LIMITATIONS Lack of information about diagnoses and potential confounders, as well as other covariates that may differ between minimal and consistent medication purchasers, are limitations to this study. CONCLUSIONS In this longitudinal study of anticonvulsant purchasers likely to have psychiatric disorders, consistent anticonvulsant treatment was associated with decreased risk of completed suicide.

Measurement of Treatment Adherence with Antipsychotic Agents in Patients with Schizophrenia

The importance of medication adherence in sustaining control of schizophrenic symptoms has generated a great deal of interest in comparing levels of treatment adherence with different antipsychotic agents. However, the bulk of the research has yielded results that are often inconsistent. In this prospective, observational study, we assessed the measurement properties of 3 commonly used, pharmacy-based measures of treatment adherence with antipsychotic agents in schizophrenia using data from the Veterans Health Administration during 2000 to 2005. Patients were selected if they were on antipsychotics and diagnosed with schizophrenia (N = 18,425). A gap of ≥30 days (with no filled index medication) was used to define discontinuation of treatment as well as medication “episodes,” or the number of times a patient returned to the same index agent after discontinuation of treatment within a 1-year period. The study found that the 3 existing measures differed in their approaches in measuring treatment adherence, suggesting that studies using these different measures would generate different levels of treatment adherence across antipsychotic agents. Considering the measurement problems associated with each existing approach, we offered a new, medication episode-specific approach, which would provide a fairer comparison of the levels of treatment adherence across different antipsychotic agents.

Is DSM-IV criterion A2 associated with PTSD diagnosis and symptom severity?

The diagnostic criteria for posttraumatic stress disorder (PTSD) have received significant scrutiny. Several studies have investigated the utility of Criterion A2, the subjective emotional response to a traumatic event. The American Psychiatric Association (APA) has proposed elimination of A2 from the PTSD diagnostic criteria for DSM-5; however, there is mixed support for this recommendation and few studies have examined A2 in samples at high risk for PTSD such as veterans. In the current study of 908 veterans who screened positive for a traumatic event, A2 was not significantly associated with having been told by a doctor that the veteran had PTSD. Those who endorsed A2, however, reported greater PTSD symptom severity in the 3 DSM-IV symptom clusters of reexperiencing (d = 0.45), avoidance (d = 0.61), and hyperarousal (d = 0.44), and A2 was significantly associated with PTSD symptom severity for all 3 clusters (R(2) = .25, .25, and .27, respectively) even with trauma exposure in the model. Thus, although A2 may not be a necessary criterion for PTSD diagnosis, its association with PTSD symptom severity warrants further exploration of its utility.

Weight gain during olanzapine treatment for psychotic depression: effects of dose and age

Weight gain has often been associated with olanzapine treatment, yet little is known about the influence of patient age or cumulative dose on olanzapine-associated weight gain. The first 118 participants in the National Institutes of Mental Health Study of the Pharmacotherapy of Psychotic Depression randomized clinical trial (Clinical Trials.gov Registration NCT00056472) completing at least 4 weeks of treatment with olanzapine were analyzed to determine the relationship between weight gain, age, and cumulative olanzapine dose. Younger (age 18–59 years) and older (age 60+ years) participants received open-label olanzapine and either sertraline or placebo for up to 12 weeks. Linear mixed effect regression modeling was used to determine the effects of age and cumulative olanzapine dose on weight gain, controlling for potential confounders. Age was observed to have a significant negative association with weight gain (P=0.01), even after controlling for differences in cumulative dose and baseline body mass index. Each 10-year increase in age was associated with a decrease in mean weight gain over 12 weeks of approximately 0.6 kg (95% confidence interval: 0.14–1.05 kg). Cumulative olanzapine dose was also significantly associated with weight gain (P<0.0001). Approximately 60% of completers of the 12-week trial experienced clinically significant weight gain (≥7% of baseline weight).