Lithium for Suicidal Behavior in Mood Disorders

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