INTRODUCTION: Mood disorders, bipolar disorder and recurrent unipolar depression, are among the most common mental health conditions worldwide. Patients with mood conditions are considered a high-risk group for cognitive impairment. Specifically, the risk estimates for developing dementia range from 1.90 to 3.02 for MDD, and 2.36 to 5.58 for mood conditions. Mild cognitive impairment (MCI), is an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. On the other hand, Lithium has long been recognized as the gold standard treatment for mood conditions and the eventual effect as neurocognitive agent. It has been reported that long-term treatment with lithium decreased the prevalence of dementia compared to patients not receiving lithium treatment. The prevalence of Alzheimer is lower in patients with bipolar disorder who are on chronic lithium therapy compared to those who are not, and low-dose lithium (from 300 mcgr to 50 mg/day) may provide neuroprotective benefits without significant side effects. This trace dosage is hypothesized to be sufficient to activate neuroprotective pathways while minimizing toxicity.
AIM: to investigate the effect of trace dosage of lithium on cognitive function in individuals at risk of developing these conditions. Specifically, this study will randomize healthy participants and patients with mild cognitive impairment to receive either a low-dose lithium supplement (50 mg daily) or a placebo, with the primary outcome being the incidence of MCI or worsening of the preexisting MCI.
HYPOTHESIS: Patients with mood conditions exposed to trace lithium dosage will have a smaller incidence of MCI or less worsening of the preexisting MCI compared with patients receiving placebo.
GOALS: A)To examine the effectiveness of lithium in prevention of mild cognitive impairment in patients with the high-risk factor of preexisting mood illnesses (i.e., unipolar depression or bipolar illness). The primary outcome is incidence of newly diagnosed mild cognitive impairment (MCI) or worsening of preexisting MCI. B) To assess, in an exploratory analysis, the clinical predictors of good lithium response in this sample. These analyses will also assess lithium effects on suicide, mortality, quality of life, functional impairment, and overall medical morbidity.
METHODOLOGY: The study will be double-blind randomized placebo-controlled trial. Patients will be recruited from two sites in Santiago, Chile, the Psychiatric Institute Dr. José Horwitz Barak and the Psychiatric Clinic of the University of Chile. Subjects aged 55 to 75 years, who present mood disorders and are not currently on lithium therapy, will be invited to participate. Inclusion Criteria are: Age 55-75, DSM-5 diagnosis of major depressive disorder or bipolar disorder (types I or II), current or lifetime, prior to participation in this study, each subject must sign an informed consent. Exclusion Criteria are: current mood treatment with lithium, alcohol dependency within the past month, current serious unstable medical conditions or history of medical illness that would contraindicate a trial of lithium, current or past severe kidney disease or baseline creatinine higher than 1.5 mg/dl, active suicidal ideation with plan and intent (Columbia Suicide Severity Rating Scale Screen Version (C-SSRS Screen) higher than points), current or past severe thyroid disease or baseline TSH higher than 5.0 uUI/dl, current diagnosis of dementia of any kind. Participants will be randomized into one of two arms: a trace dose lithium or placebo, each group consisting of 125 subjects. Block randomization will be stratified by diagnosis (bipolar vs MDD), gender, decade of age, and presence or absence of any baseline cognitive impairment Interventions. All participants will receive their usual clinical medical treatment during the time the study is conducted. All psychotropic medications will be allowed to be given per standard of care except lithium. The study defined randomization to lithium or placebo arms as adjuncts to other medications. Intervention arm will consist in lithium 50 mg oral tablets per day (trace doses). Control arm will consist in placebo tablet.
OUTCOME: The primary outcome measure will be the incidence of Mild Cognitive Impairment (MCI) or worsening of preexisting MCI at one, three, and four years. This primary outcome will be defined as change from patients initially with a Clinical Dementia Rating Scale (CDR) score of 0 to 0.5 (MCI) or patients initially with a score in the CDR of 0.5 that change to 1. (worsening of MCI). The primary analysis will employ a Cox regression model to analyze the time to first clinical diagnosis of MCI or worsening of MCI.
Age 55-70.
DSM-5 diagnosis of major depressive disorder or bipolar disorder (types I or II), current or lifetime.
Prior to participation in this study, each subject must sign an informed consent.
Current mood treatment with lithium.
Alcohol dependency within the past month.
Current serious unstable medical conditions or history of medical illness that would contraindicate a trial of lithium.
Current or past severe kidney disease or baseline creatinine > 1.5 mg/dl.
Parallel
Trace lithium dose plus treatment as usual
DrugSubjects assigned to the active arm will receive 50 mg of lithium per day, for five years
Placebo pill plus treatment as usual
DrugPatients will receive a placebo pill plus treatment as usual by their clinical providers
Incidence of MCI
Incidence of Mild Cognitive Impairment (MCI) on a yearly basis from year one until the end of the study (year five). This primary outcome will be defined as change from patients initially with a Clinical Dementia Rating Scale (CDR) score of 0 to 0.5 (MCI). The Clinical Dementia Rating Scale is a numerical scale used to quantify the severity of symptoms of dementia. It is used for assessing six cognitive and functional domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR scale helps in categorizing the stages of dementia from no dementia (CDR 0) to severe dementia (CDR 3), providing a standardized measure for the severity of dementia. The primary analysis will employ a Cox regression model to analyze the time to first clinical diagnosis of MCI.
Clinical predictors of lithium response
Sheehan Disability Scale (SDS): is a self-administered psychological assessment tool that measures functional impairment in three inter-related domains: work/school, social, and family life. Developed by Dr. David Sheehan, the SDS is commonly used to evaluate the extent to which mental health symptoms disrupt daily functions and responsibilities. It has five items with a Likert scale from 0 (not at all) to 10 (extremely). Total score 0: lack of disability Total score 1-3: mild disability Total score 4-6: moderate disability Total score 7-10: extreme disability
Clinical predictors of lithium response
Columbia Suicide Severity Rating Scale (C-SSRS): A tool used for the assessment of suicidal ideation and behavior. It is designed to evaluate the severity of suicidal ideation and the presence of suicidal behavior in individuals. The scale has been widely adopted in clinical and research settings due to its sensitivity in identifying varying degrees of suicidality and its ability to support timely interventions. It has six self reported YES/NO questions addressing different context to determine low, moderate and high risk of suicide.
Clinical predictors of lithium response
Patient Health Questionnaire-9 (PHQ-9): A widely used nine-item self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. The scores range from 0 to 27, with a score of 10 or more indicative of a possible clinically significant depression. The PHQ-9 was validated in Chile. It consist of nine self reported items, four-point scale from 0 (never) to 3 (almost every day) each. Total score less than 5: absence of a depressive disorder Total score 5 to 9: no depression or sub-threshold depression Total scores of 10 to 14: spectrum of depression Total scores of 15 or greater: major depression
Clinical predictors of lithium response
Altman Self-Rating Mania Scale (ASMS): Self-report questionnaire used to assess the presence and severity of mania symptoms. It is commonly used in both clinical and research settings to monitor manic episodes in individuals with mood disorders. The scale consists of five items scoring from 0 to 4 each, including elevated mood, increased energy, reduced need for sleep, and hyperactivity. Total total score 15-20: mild mania Total score 21 -28: moderate mania Total score 29-32: marked mania Total score 33 - 43: severe mania Total score ≥44: extreme mania
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