Li+: Lithium for Suicidal Behavior in Mood Disorders

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Terminated
• CT.gov ID: NCT01928446
• Collaborator: (none)
• Enrollment: 519
• Locations: 28
• Arms: 2
• Actual Duration (Months): 53.4
• Patients Per Site: 18.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Bipolar Disorder; Suicide; Suicide, Attempted	Drug: Lithium; Drug: Placebo	Phase 2/Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 519 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: CSP #590 - Lithium for Suicidal Behavior in Mood Disorders
• Actual Study Start Date: Jul 8, 2015
• Actual Primary Completion Date: Dec 19, 2019
• Actual Study Completion Date: Dec 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lithium Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).	Drug: Lithium; Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).
Placebo Comparator: Placebo Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study	Drug: Placebo; Oral placebo tablets will be administered for the duration of follow-up (1 year).

Outcome Measures

Primary Outcome Measures

1. Time to Event Hazard Rate. Event is a First Repeated Episode of Suicide Related Event, Including Suicide Attempts, Interrupted Attempts and Hospitalizations for Prevention of Attempts. [1 year]

   The primary hypothesis tested is that lithium augmentation of enhanced usual care is superior to enhanced usual care plus placebo for the prevention of repeated episodes of suicidal self-directed violence over time. The investigators posit a one-year repeat rate of 15% in the placebo group and a 37% reduction of events in the intervention group. Suicidal self-directed violence includes non-fatal suicide attempts, interrupted attempts (attempts interrupted by patient or by others), hospitalization to prevent suicide and deaths from suicide.

2. Number of Compliant Participants With Episode of Self-directed Violence (Per Protocol Analyses) [1 year]

   Compliance is defined as taking 80% or more of study medication over the entire clinical trial. Episode of self-directed violence is defined as: First Repeated Episode of Suicide Related Event, Including Suicide Attempts, Interrupted Attempts, Hospitalization to Prevent Suicide and death.

Secondary Outcome Measures

1. Number of Participants With Subtypes of Suicidal Self-directed Violence for All Recurring Events [1 year]

   Subtypes of suicidal self-directed violence: Self-directed violence; Interrupted self-directed violence; Hospitalization to prevent suicide; Death from suicide - there were too few deaths in the study, making data insufficient to perform analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix VA Health Care System, Phoenix, AZ	Phoenix	Arizona	United States	85012
2	Southern Arizona VA Health Care System, Tucson, AZ	Tucson	Arizona	United States	85723
3	Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR	North Little Rock	Arkansas	United States	72114-1706
4	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California	United States	92357
5	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California	United States	94304-1290
6	VA San Diego Healthcare System, San Diego, CA	San Diego	California	United States	92161
7	VA Eastern Colorado Health Care System, Denver, CO	Denver	Colorado	United States	80220
8	Miami VA Healthcare System, Miami, FL	Miami	Florida	United States	33125
9	Orlando VA Medical Center, Orlando, FL	Orlando	Florida	United States	32803
10	Atlanta VA Medical and Rehab Center, Decatur, GA	Decatur	Georgia	United States	30033
11	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois	United States	60141-5000
12	Richard L. Roudebush VA Medical Center, Indianapolis, IN	Indianapolis	Indiana	United States	46202-2884
13	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts	United States	02130
14	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota	United States	55417
15	VA Southern Nevada Healthcare System, North Las Vegas, NV	Las Vegas	Nevada	United States	89106
16	VA Sierra Nevada Health Care System, Reno, NV	Reno	Nevada	United States	89502
17	Asheville VA Medical Center, Asheville, NC	Asheville	North Carolina	United States	28805
18	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio	United States	44106
19	VA Portland Health Care System, Portland, OR	Portland	Oregon	United States	97239
20	Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania	United States	19104
21	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania	United States	15240
22	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas	United States	75216
23	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas	United States	77030
24	Central Texas Veterans Health Care System, Temple, TX	Temple	Texas	United States	76504
25	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah	United States	84148
26	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington	United States	98108
27	William S. Middleton Memorial Veterans Hospital, Madison, WI	Madison	Wisconsin	United States	53705
28	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin	United States	53295-1000

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Study Chair: Ira R Katz, MD PhD, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Study Documents (Full-Text)

• Study Protocol - Sep 3, 2019
• Statistical Analysis Plan - Apr 1, 2016
• Informed Consent Form: Screening ICF - May 1, 2018
• Informed Consent Form: Randomization ICF - May 1, 2018

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01928446
• Other Study ID Numbers: 590
• First Posted: Aug 26, 2013
• Last Update Posted: Jun 24, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by VA Office of Research and Development: Lithium; Placebo; Double-blind methods; Clinical Trials, Randomized; Veterans
• Additional relevant MeSH terms: Disease; Depressive Disorder; Bipolar Disorder; Suicide; Mood Disorders; Suicide, Attempted; Lithium Carbonate

Study Results

Participant Flow

Pre-assignment Detail	Assessed for eligibility (n=21887). Signed 1st consent (n=722); Excluded: did not meet inclusion criteria (n= 173). Signed 2nd consent (n=599); Excluded: not randomized (n=78); assigned to treatment arm, but dropped out prior to receiving Study Meds (n=2).

Arm/Group Title	Lithium	Placebo
Arm/Group Description	Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).	Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study
Period Title: Overall Study
STARTED	255	264
COMPLETED	144	125
NOT COMPLETED	111	139

Baseline Characteristics

Arm/Group Title	Lithium	Placebo	Total
Arm/Group Description	Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).	Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study	Total of all reporting groups
Overall Participants	255	264	519
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.2 (12.4)	42.4 (12.4)	42.8 (12.4)
Sex: Female, Male (Count of Participants)
Female	43 16.9%	39 14.8%	82 15.8%
Male	212 83.1%	225 85.2%	437 84.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	35 13.7%	42 15.9%	77 14.8%
Not Hispanic or Latino	220 86.3%	217 82.2%	437 84.2%
Unknown or Not Reported	0 0%	5 1.9%	5 1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 2%	4 1.5%	9 1.7%
Asian	4 1.6%	1 0.4%	5 1%
Native Hawaiian or Other Pacific Islander	4 1.6%	3 1.1%	7 1.3%
Black or African American	39 15.3%	44 16.7%	83 16%
White	185 72.5%	192 72.7%	377 72.6%
More than one race	10 3.9%	8 3%	18 3.5%
Unknown or Not Reported	8 3.1%	12 4.5%	20 3.9%

Outcome Measures

1. Primary Outcome

Title	Time to Event Hazard Rate. Event is a First Repeated Episode of Suicide Related Event, Including Suicide Attempts, Interrupted Attempts and Hospitalizations for Prevention of Attempts.
Description	The primary hypothesis tested is that lithium augmentation of enhanced usual care is superior to enhanced usual care plus placebo for the prevention of repeated episodes of suicidal self-directed violence over time. The investigators posit a one-year repeat rate of 15% in the placebo group and a 37% reduction of events in the intervention group. Suicidal self-directed violence includes non-fatal suicide attempts, interrupted attempts (attempts interrupted by patient or by others), hospitalization to prevent suicide and deaths from suicide.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium	Placebo
Arm/Group Description	Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).	Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study
Measure Participants	255	264
Number [Monthly Hazard rate]	0.0382	0.0348

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments	Model1 - Treatment only: unadjusted for other covariates
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments	Model2 - Treatment only: unadjusted with Site as random Effect
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Compliant Participants With Episode of Self-directed Violence (Per Protocol Analyses)
Description	Compliance is defined as taking 80% or more of study medication over the entire clinical trial. Episode of self-directed violence is defined as: First Repeated Episode of Suicide Related Event, Including Suicide Attempts, Interrupted Attempts, Hospitalization to Prevent Suicide and death.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Analysis performed for a subset of participants: 88 of 519 subjects took 80% or more of their study medication (46 on lithium, 42 on placebo) and were considered substantially compliant. Twenty of these subjects had primary outcomes (8 on placebo, 12 on lithium).

Arm/Group Title	Lithium (Compliance Per Protocol)	Placebo (Compliance Per Protocol)
Arm/Group Description	compliance with study medication, defined as taking 80% or more of their study medication	compliance with study medication, defined as taking 80% or more of their study medication
Measure Participants	46	42
Count of Participants [Participants]	12 4.7%	8 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.61 to 3.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Subtypes of Suicidal Self-directed Violence for All Recurring Events
Description	Subtypes of suicidal self-directed violence: Self-directed violence; Interrupted self-directed violence; Hospitalization to prevent suicide; Death from suicide - there were too few deaths in the study, making data insufficient to perform analysis.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium	Placebo
Arm/Group Description	Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).	Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study
Measure Participants	255	264
Suicidal self-directed violence	11 4.3%	10 3.8%
Interrupted suicidal self-directed violence	17 6.7%	11 4.2%
Hospitalization to prevent suicide	34 13.3%	39 14.8%
Death from suicide	1 0.4%	0 0%
Other	2 0.8%	2 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments	Model 5: Non-fatal self-directed violence subgroup
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.48 to 2.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments	Model 6: Interrupted self-directed violence subgroup
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.75 to 3.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lithium, Placebo
	Comments	Model 7: Hospitalization to prevent suicide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Data collected over 395 days from randomization
Arm/Group Title	Lithium		Placebo
Arm/Group Description	Lithium in the form of extended release lithium carbonate. Subjects will be started on 600 mg/day (300mg bid) until steady state at target plasma levels between 0.6 and 0.8 meq/liter is achieved. The lowest dose will be 300 mg/day. Lithium will be prescribed for the duration of follow-up (1 year).		Placebo tablets will be given to the subjects for the duration of follow-up (1 year). Dose adjustments will mimic the intervention arm of the study
All Cause Mortality
	Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/255 (0.4%)		3/264 (1.1%)
Serious Adverse Events
	Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/255 (38.8%)		90/264 (34.1%)
Cardiac disorders
Acute myocardial infarction	1/255 (0.4%)	1	0/264 (0%)	0
Angina unstable	1/255 (0.4%)	1	0/264 (0%)	0
Atrial fibrillation	0/255 (0%)	0	1/264 (0.4%)	1
Bundle branch block right	0/255 (0%)	0	1/264 (0.4%)	1
Myocardial infarction	1/255 (0.4%)	1	0/264 (0%)	0
Pericarditis	0/255 (0%)	0	1/264 (0.4%)	2
Supraventricular tachycardia	1/255 (0.4%)	1	0/264 (0%)	0
Tachycardia	1/255 (0.4%)	1	0/264 (0%)	0
Eye disorders
Blindness	1/255 (0.4%)	1	0/264 (0%)	0
Gastrointestinal disorders
Constipation	1/255 (0.4%)	1	1/264 (0.4%)	1
Crohn's disease	2/255 (0.8%)	2	0/264 (0%)	0
Diarrhoea	1/255 (0.4%)	1	0/264 (0%)	0
Dyspepsia	0/255 (0%)	0	1/264 (0.4%)	1
Inguinal hernia	0/255 (0%)	0	1/264 (0.4%)	1
Mesenteric panniculitis	1/255 (0.4%)	1	0/264 (0%)	0
Nausea	0/255 (0%)	0	1/264 (0.4%)	1
Umbilical hernia	1/255 (0.4%)	1	0/264 (0%)	0
General disorders
Chest pain	3/255 (1.2%)	3	2/264 (0.8%)	2
Death	1/255 (0.4%)	1	1/264 (0.4%)	1
Hypothermia	1/255 (0.4%)	1	0/264 (0%)	0
Non-cardiac chest pain	2/255 (0.8%)	2	1/264 (0.4%)	1
Pain	1/255 (0.4%)	1	0/264 (0%)	0
Serositis	1/255 (0.4%)	1	0/264 (0%)	0
Unevaluable event	1/255 (0.4%)	1	0/264 (0%)	0
Infections and infestations
Abscess limb	0/255 (0%)	0	1/264 (0.4%)	1
Appendicitis	1/255 (0.4%)	1	0/264 (0%)	0
Bronchitis	1/255 (0.4%)	1	0/264 (0%)	0
Cellulitis	0/255 (0%)	0	1/264 (0.4%)	1
Diverticulitis	1/255 (0.4%)	1	0/264 (0%)	0
Folliculitis	0/255 (0%)	0	1/264 (0.4%)	1
Gastroenteritis	0/255 (0%)	0	1/264 (0.4%)	1
Infection	0/255 (0%)	0	1/264 (0.4%)	1
Localised infection	0/255 (0%)	0	1/264 (0.4%)	1
Lower respiratory tract infection	1/255 (0.4%)	1	0/264 (0%)	0
Paronychia	0/255 (0%)	0	1/264 (0.4%)	1
Pneumonia	0/255 (0%)	0	3/264 (1.1%)	3
Postoperative wound infection	0/255 (0%)	0	1/264 (0.4%)	1
Sepsis	1/255 (0.4%)	1	1/264 (0.4%)	1
Subcutaneous abscess	1/255 (0.4%)	1	0/264 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	0/255 (0%)	0	1/264 (0.4%)	1
Alcohol poisoning	4/255 (1.6%)	6	0/264 (0%)	0
Animal bite	1/255 (0.4%)	1	0/264 (0%)	0
Concussion	0/255 (0%)	0	1/264 (0.4%)	1
Contusion	1/255 (0.4%)	1	0/264 (0%)	0
Craniocerebral injury	2/255 (0.8%)	2	1/264 (0.4%)	1
Facial bones fracture	0/255 (0%)	0	1/264 (0.4%)	1
Intentional overdose	0/255 (0%)	0	1/264 (0.4%)	1
Joint dislocation	0/255 (0%)	0	1/264 (0.4%)	1
Limb injury	0/255 (0%)	0	1/264 (0.4%)	1
Overdose	2/255 (0.8%)	2	2/264 (0.8%)	2
Product administration error	1/255 (0.4%)	1	0/264 (0%)	0
Rectal injury	0/255 (0%)	0	1/264 (0.4%)	1
Road traffic accident	1/255 (0.4%)	1	1/264 (0.4%)	1
Scrotal haematoma	0/255 (0%)	0	1/264 (0.4%)	1
Skin laceration	1/255 (0.4%)	1	1/264 (0.4%)	1
Sternal fracture	0/255 (0%)	0	1/264 (0.4%)	1
Investigations
Antipsychotic drug level increased	1/255 (0.4%)	1	0/264 (0%)	0
Blood pressure increased	0/255 (0%)	0	1/264 (0.4%)	1
Glomerular filtration rate abnormal	1/255 (0.4%)	1	0/264 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	0/255 (0%)	0	1/264 (0.4%)	1
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis	0/255 (0%)	0	1/264 (0.4%)	1
Costochondritis	1/255 (0.4%)	1	0/264 (0%)	0
Intervertebral disc protrusion	1/255 (0.4%)	1	0/264 (0%)	0
Joint effusion	0/255 (0%)	0	1/264 (0.4%)	1
Lumbar spinal stenosis	0/255 (0%)	0	1/264 (0.4%)	1
Muscular weakness	1/255 (0.4%)	1	0/264 (0%)	0
Musculoskeletal pain	1/255 (0.4%)	1	0/264 (0%)	0
Osteoarthritis	1/255 (0.4%)	1	0/264 (0%)	0
Rhabdomyolysis	0/255 (0%)	0	1/264 (0.4%)	1
Nervous system disorders
Arachnoid cyst	0/255 (0%)	0	1/264 (0.4%)	1
Carpal tunnel syndrome	0/255 (0%)	0	1/264 (0.4%)	1
Cerebrovascular accident	0/255 (0%)	0	2/264 (0.8%)	2
Encephalopathy	0/255 (0%)	0	1/264 (0.4%)	1
Headache	1/255 (0.4%)	3	0/264 (0%)	0
Hemiparesis	2/255 (0.8%)	3	0/264 (0%)	0
Hypoaesthesia	1/255 (0.4%)	3	0/264 (0%)	0
Loss of consciousness	1/255 (0.4%)	1	0/264 (0%)	0
Lumbar radiculopathy	1/255 (0.4%)	1	1/264 (0.4%)	1
Migraine	1/255 (0.4%)	1	0/264 (0%)	0
Multiple sclerosis	0/255 (0%)	0	1/264 (0.4%)	1
Seizure	1/255 (0.4%)	1	3/264 (1.1%)	4
Syncope	1/255 (0.4%)	1	3/264 (1.1%)	3
Transient ischaemic attack	1/255 (0.4%)	2	0/264 (0%)	0
Tremor	1/255 (0.4%)	1	0/264 (0%)	0
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/255 (0.4%)	1	0/264 (0%)	0
Psychiatric disorders
Adjustment disorder	0/255 (0%)	0	1/264 (0.4%)	1
Adjustment disorder with depressed mood	2/255 (0.8%)	3	0/264 (0%)	0
Affective disorder	3/255 (1.2%)	4	1/264 (0.4%)	1
Alcohol withdrawal syndrome	1/255 (0.4%)	1	2/264 (0.8%)	6
Alcoholism	10/255 (3.9%)	14	10/264 (3.8%)	22
Bipolar I disorder	1/255 (0.4%)	1	2/264 (0.8%)	3
Bipolar II disorder	2/255 (0.8%)	2	0/264 (0%)	0
Bipolar disorder	1/255 (0.4%)	1	0/264 (0%)	0
Borderline personality disorder	2/255 (0.8%)	2	0/264 (0%)	0
Completed suicide	0/255 (0%)	0	1/264 (0.4%)	1
Depression	7/255 (2.7%)	8	7/264 (2.7%)	12
Drug use disorder	0/255 (0%)	0	1/264 (0.4%)	1
Hallucinations, mixed	1/255 (0.4%)	1	0/264 (0%)	0
Homicidal ideation	0/255 (0%)	0	1/264 (0.4%)	1
Intentional self-injury	2/255 (0.8%)	3	3/264 (1.1%)	3
Major depression	12/255 (4.7%)	12	13/264 (4.9%)	15
Mania	1/255 (0.4%)	1	1/264 (0.4%)	1
Narcissistic personality disorder	1/255 (0.4%)	1	0/264 (0%)	0
Panic attack	2/255 (0.8%)	2	0/264 (0%)	0
Post-traumatic stress disorder	7/255 (2.7%)	8	11/264 (4.2%)	12
Psychotic disorder	0/255 (0%)	0	1/264 (0.4%)	1
Schizoaffective disorder	1/255 (0.4%)	1	1/264 (0.4%)	1
Substance use disorder	5/255 (2%)	5	5/264 (1.9%)	5
Substance-induced mood disorder	2/255 (0.8%)	2	1/264 (0.4%)	1
Substance-induced psychotic disorder	3/255 (1.2%)	3	0/264 (0%)	0
Suicidal ideation	9/255 (3.5%)	11	18/264 (6.8%)	24
Suicide attempt	16/255 (6.3%)	20	10/264 (3.8%)	10
Suicide threat	0/255 (0%)	0	1/264 (0.4%)	1
Violence-related symptom	2/255 (0.8%)	2	0/264 (0%)	0
Renal and urinary disorders
Hydronephrosis	0/255 (0%)	0	1/264 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/255 (0%)	0	1/264 (0.4%)	1
Chronic obstructive pulmonary disease	2/255 (0.8%)	3	0/264 (0%)	0
Oropharyngeal pain	1/255 (0.4%)	1	0/264 (0%)	0
Pulmonary embolism	1/255 (0.4%)	1	0/264 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	1/255 (0.4%)	1	0/264 (0%)	0
Social circumstances
Bereavement	0/255 (0%)	0	1/264 (0.4%)	2
Surgical and medical procedures
Alcohol detoxification	3/255 (1.2%)	3	4/264 (1.5%)	7
Alcohol rehabilitation	0/255 (0%)	0	2/264 (0.8%)	2
Cardiac pacemaker insertion	0/255 (0%)	0	1/264 (0.4%)	1
Carpal tunnel decompression	1/255 (0.4%)	1	0/264 (0%)	0
Hernia hiatus repair	0/255 (0%)	0	1/264 (0.4%)	1
Hysterectomy	0/255 (0%)	0	1/264 (0.4%)	1
Leg amputation	0/255 (0%)	0	1/264 (0.4%)	1
Mass excision	0/255 (0%)	0	1/264 (0.4%)	1
Nasal septal operation	0/255 (0%)	0	1/264 (0.4%)	1
Penile prosthesis insertion	2/255 (0.8%)	2	0/264 (0%)	0
Prostatectomy	0/255 (0%)	0	1/264 (0.4%)	1
Transurethral prostatectomy	0/255 (0%)	0	1/264 (0.4%)	1
Wrist surgery	1/255 (0.4%)	1	0/264 (0%)	0
Other (Not Including Serious) Adverse Events
	Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	193/255 (75.7%)		166/264 (62.9%)
Gastrointestinal disorders
Diarrhoea	58/255 (22.7%)	70	41/264 (15.5%)	50
Dry mouth	12/255 (4.7%)	12	14/264 (5.3%)	14
Nausea	40/255 (15.7%)	48	26/264 (9.8%)	30
Vomiting	14/255 (5.5%)	15	6/264 (2.3%)	7
General disorders
Fatigue	23/255 (9%)	24	7/264 (2.7%)	7
Thirst	28/255 (11%)	33	23/264 (8.7%)	24
Investigations
Electrocardiogram QT prolonged	14/255 (5.5%)	16	5/264 (1.9%)	7
Glomerular filtration rate decreased	34/255 (13.3%)	41	22/264 (8.3%)	32
Metabolism and nutrition disorders
Decreased appetite	12/255 (4.7%)	13	15/264 (5.7%)	15
Weight fluctuation	9/255 (3.5%)	10	21/264 (8%)	22
Nervous system disorders
Dizziness	23/255 (9%)	26	14/264 (5.3%)	16
Headache	30/255 (11.8%)	32	33/264 (12.5%)	35
Somnolence	18/255 (7.1%)	18	30/264 (11.4%)	35
Tremor	61/255 (23.9%)	72	19/264 (7.2%)	19
Renal and urinary disorders
Pollakiuria	22/255 (8.6%)	25	21/264 (8%)	23

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.