Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Improving participation in clinical trials of novel therapies: going back to basics.

Clinical trials in many diseases are experiencing more difficulties in achieving sufficient or timely enrollment of participants; anecdotal reports from trials of novel therapies for systemic lupus erythematosus (SLE) seem to be facing the same challenges. General factors associated with this trend include the growth of the contract research industry, increasing oversight, and high-profile accounts of scientific misconduct and fraud in research. Complicated protocols that increase participant burden, overly restrictive entry criteria, the fear of an SLE flare may also affect enrollment in SLE trials.

A randomized clinical trial of a psychoeducational intervention to improve outcomes in systemic lupus erythematosus.

OBJECTIVE: In a cross-sectional study, we previously identified 2 potentially modifiable risk factors for adverse outcomes in systemic lupus erythematosus (SLE): self-efficacy and social support. The goal of this study was to evaluate in a randomized controlled trial a theory-based intervention to improve patient self-efficacy and partner support to manage SLE. METHODS: Patients with SLE ages 18 years and older who met the American College of Rheumatology criteria and were able to identify a partner (spouse or family member) were recruited from 2 academic medical centers and randomized into an experimental group or a control group. Patients in the experimental group and their partners received an intervention designed to enhance self-efficacy, couples communication about lupus, social support, and problem solving, in the form of a 1-hour session with a nurse educator followed by monthly telephone counseling for 6 months. Patients in the control group and their partners received an attention placebo, including a 45-minute video presentation about lupus, and monthly telephone calls. Measures of physical and mental health status, disease activity, and psychosocial factors were collected at baseline, 6 months, and 12 months. The effect of the intervention on physical and mental health and disease activity at 6 and at 12 months was modeled with linear regression and adjusted for baseline health status, disease activity, sociodemographic factors, treatment change, and psychosocial factors. RESULTS: One hundred twenty-two patients (plus their partners) were enrolled and randomized as follows: 64 to the experimental intervention and 58 to the attention control group. The participants were predominantly white, approximately half were college educated, and the groups were balanced for sociodemographic factors. At 6 months, significantly higher scores for couples communication (P = 0.01) and problem-focused coping (P = 0.03) were seen in the experimental group compared with the control group. At 12 months (6 months after the intervention ended), social support was higher (4.4 versus 4.1; P = 0.03), self-efficacy was higher (7.2 versus 6.2; P = 0.02), couples communication was higher (3.5 versus 3.1; P = 0.03), and fatigue was lower (5.1 versus 6.3; P = 0.02) in the experimental group compared with the control group. Global mental health status at 12 months, as measured by the Short Form 36 survey, was 69 points in the experimental group compared with 58 points in the control group (P = 0.04). In multivariate models, adjusting for baseline covariates, scores for couple communication (P = 0.01) were significantly higher at 6 months, and scores for self-efficacy (P = 0.004) and global mental health status (P = 0.03) were significantly higher at 12 months in the experimental group compared with the control group, and the mean score for global physical function was higher by 7 points, which was a clinically meaningful change (P = 0.2). The mean score for fatigue was also significantly lower in the experimental group than in the control group (P = 0.05). SLE disease activity was unchanged by this intervention. CONCLUSION: This randomized, controlled trial of a theory-based educational intervention in SLE demonstrated significantly higher scores for couple communication, self-efficacy, and mental health status, and lower fatigue scores in the experimental group compared with the control group. Because couple communication and self-efficacy appear to be modifiable risk factors, they may also be potential targets in more disadvantaged populations.

Neuropsychiatric systemic lupus erythematosus, age, and the neurodevelopmental model: evidence in support of the Weinberger hypothesis.

We set out to describe neurologic and psychiatric syndromes secondary to systemic lupus erythematosus (NPSLE) in terms of age of onset and to compare such findings to those predicted by Weinberger's "windows of vulnerability" hypothesis of the neurodevelopmental pathogenesis of mental disorders. A search of the literature provided 767 NPSLE diagnoses in 511 patients. The particular NPSLE diagnoses and the age at which they occurred were compiled. We then determined ranges, medians, and means of age of onset of the various syndromes. We compared these to the ranges and means of age of onset of psychiatric disorders postulated in the "windows" model. The type of NPSLE varied with age and the most striking finding was an 11.3-year difference between the mean onset of psychosis (30.4) and depressed mood (41.1). The mean ages of onset and the ranges were similar to those proposed by Weinberger both absolutely and in temporal relation to each other. We conclude that NPSLE syndromes vary in age of onset in a manner consistent with, and in support of, the "windows of vulnerability" neurodevelopmental model of mental disorders.

Nonspecific medication side effects and the nocebo phenomenon.

Patients taking active medications frequently experience adverse, nonspecific side effects that are not a direct result of the specific pharmacological action of the drug. Although this phenomenon is common, distressing, and costly, it is rarely studied and poorly understood. The nocebo phenomenon, in which placebos produce adverse side effects, offers some insight into nonspecific side effect reporting. We performed a focused review of the literature, which identified several factors that appear to be associated with the nocebo phenomenon and/or reporting of nonspecific side effects while taking active medication: the patient's expectations of adverse effects at the outset of treatment; a process of conditioning in which the patient learns from prior experiences to associate medication-taking with somatic symptoms; certain psychological characteristics such as anxiety, depression, and the tendency to somatize; and situational and contextual factors. Physicians and other health care personnel can attempt to ameliorate nonspecific side effects to active medications by identifying in advance those patients most at risk for developing them and by using a collaborative relationship with the patient to explain and help the patient to understand and tolerate these bothersome but nonharmful symptoms.