terminated early due to non-safety related DMC recommendations

Observational evidence and findings from clinical trials conducted for other reasons suggest that lithium, a drug used for the treatment of bipolar disorder, and, to a lesser extent, depression, may reduce rates of suicides and suicide attempts. However, this hypothesis has not yet been adequately examined in a randomized clinical trial conducted specifically to test lithium's efficacy in preventing suicides. This clinical trial fills this gap.

This study is feasible within the Department of Veterans Affairs (VA) because it is a large, integrated health system with existing programs for identifying patients at risk for suicide and delivering enhanced services. In VA, approximately 12,000 patients with depression or bipolar disorder survive a suicide attempt or related behavior each year, and 15% of them repeat within one year. Experimental treatment in this study will supplement usual care for major depression or bipolar disorder, as well as VA's standard, enhanced management for patients at high risk.

The investigators will recruit 1862 study participants, from approximately 30 VA Hospitals. Participants will be patients with bipolar disorder or depression who have survived a recent episode of suicidal self-directed violence or were hospitalized specifically to prevent suicide. Randomly, half will receive lithium, and half will receive placebo. Neither the patients nor their doctors will know whether a particular person has received lithium or placebo. The treatment will be administered and the patients will be followed for one year, after which patients will go back to usual care. Recruitment will occur over 3 years.

The investigators are primarily interested in whether lithium leads to increases in the time to the first repeated episode of suicidal behavior, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. In addition, this study will allow us to explore whether lithium decreases the total number of suicidal behaviors, and whether it has comparable effects on impulsive and non-impulsive behaviors. If there is an effect of lithium, the investigators will be interested in whether or not it could be attributed to improved control of the underlying mental health condition, or, alternatively, whether it represents a direct effect of suicide-related behavior.

Objective: To test the hypothesis that lithium augmentation of enhanced usual care will reduce the rate of repeated episodes of suicidal self-directed violence (repeated suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event.

Background: The hypothesis that lithium can prevent suicide in patients with bipolar disorder and depression is based on data from observational studies and randomized clinical trials conducted to evaluate other outcomes. The question about the effectiveness of lithium for suicide prevention is one of major scientific, clinical, and public health significance. There have been no adequately powered clinical trials conducted specifically to evaluate suicide behaviors as an outcome. Two recent randomized clinical trials failed to recruit adequate numbers of subjects to be conclusive.

The VHA, as a large national healthcare system with an established program for identifying new suicide attempts, evaluating patients for underlying mental health and medical conditions, providing needed services, connecting Veterans to state-of-the-art suicide risk management, and monitoring outcomes is uniquely able to conduct a large scale clinical trial of lithium for suicide prevention.

The rationale for the study is based on the following:

• Data from observational studies and double-blind randomized clinical trials suggest that lithium can prevent suicide-related behaviors in patients with bipolar disorder and major depression.
• The high risk of suicide in Veterans receiving health care services from VHA has persisted despite extensive improvements in mental health services and in programs for suicide prevention.
• Each month, there are over 1,100 unique VHA patients with bipolar disorder or depression who attempt suicide and survive.
• Surviving a suicide attempt is the most powerful known risk factor for death from suicide in VA and elsewhere.
• Approximately 15% of VA survivors reattempt or die from suicide within one year.
• Evaluating rates of reattempts in those who have survived attempts is an established and effective method for testing interventions that may prevent suicide.
• Experimental treatment in CSP-590 would supplement usual care for major depression or bipolar disorder.
• Study procedures for the management of suicide risk would meet or exceed VA standards and requirements.
• Study procedures optimize the safety of lithium, including the potential risk of overdoses, and meet or exceed all published practice standards. The trial will utilize multiple strategies to minimize risks including frequent monitoring and assessment, determination of lithium levels during titration and at steady state, and dispensing medications in limited quantities in blister packs.
• The investigator's survey of VA psychiatrists indicates that the question is clinically important and compelling and that a clinical trial that demonstrated the hypothesized effect would transform the clinical management of suicidality.

Design: Randomized, double-blind, placebo-controlled clinical trial of lithium versus placebo augmentation of enhanced usual care.

Patient population: VHA patients with bipolar disorder or depression who have survived a recent episode of suicidal self-directed violence.

Primary outcome: Time to the first repeated episode of suicidal self-directed violence, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide

Duration: Total study duration will be 4.5 years. Recruitment will occur over 3 years. Participants will be followed for one year.

Sample size calculations and number of sites required: The design of the study is based on testing for a 37% reduction in the rate of repeated suicidal self-directed violence, a figure based on an effect size of approximately 43% observed in recent studies and then allowing for attenuation due to non-adherence. Adjusting for potential data loss due to attrition, 90% statistical power to detect a significant 37% reduction in reattempt rates at 5% overall type I error would require 1862 subjects. With recruitment of 20% of eligible subjects over a three year period, this would require approximately 9310 potentially eligible subjects. Based on current suicide surveillance data, this could be achieved with 29 sites.

Inclusion Criteria:

• Must be a Veteran of the United States Armed Forces
• Survived an episode of suicidal self-directed violence (including suicide attempts and interrupted attempts) that occurred within six months of admission to the study, or they were admitted within the past six months to a mental health inpatient unit specifically to prevent suicide
• Have a diagnosis of an affective disorder meeting DSM-IV-TR (2000) criteria for Bipolar I Disorder, Bipolar II Disorder, or current or recurrent Major Depressive Disorder
• Are able and willing to identify one or more family members, friends, or other contacts and give permission for both clinical providers and the Research Team to contact them if the patient cannot be reached
• Are able to provide informed consent
• There is concurrence from the patient's mental health provider about inclusion/exclusion criteria and confirmation of the providers' willingness to work with the research team in managing the patient during the course of the study. The provider responsible for the patient's general medical care has been made aware of the participation
• Must be registered at a VA Medical Center

Exclusion Criteria:

• Schizophrenia or schizoaffective disorder

• Cognitive impairment defined as a Brief Orientation Memory and Concentration Test score > 10

• Lack of decision-making capacity to evaluate the risks versus the benefits of participation as determined by Jeste's brief instrument for assessing decisional capacity, or adjudication of incompetence and the appointment of a guardian or conservator

• Six or more previous lifetime suicide attempts as ascertained through SPAN, reports from family, or patient self-report

• Current or recent (within six months) use of lithium

• History of significant adverse effects of lithium as ascertained through the medical record or self-report

• Unstable medical conditions or specific medical comorbidity:

  • Congestive heart failure by Framingham criteria
  • QTc greater than or equal to 450 ms for men and greater than or equal to 460 ms for women
  • Chronic renal failure defined by national Kidney Foundation Disease Outcome Quality Initiative (KDOQI) criteria

• Any possibility of being pregnant or not on appropriate birth control

• Lactation and breastfeeding

• Concurrent medications:

  • All diuretics except amiloride
  • Haloperidol
  • Clozapine

• Active substance abuse:

  • Active alcohol or opiate dependence requiring medically supervised withdrawal and stabilization
  • Active cocaine, methamphetamine, other stimulant, hallucinogen, or cannabis abuse requiring stabilization

• Enrollment in another randomized interventional clinical trial

Individual Participant Data will be made available after study closure only to research credentialed Veterans Affairs researchers who submit a valid study question to their IRB of record. A Data Use Agreement will be in effect between the researcher and the coordinating center