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.

Mood disorders, bipolar disorder and recurrent unipolar depression, are among the most common mental health conditions worldwide. Research estimates that the international lifetime prevalence of bipolar disorder (BD) is 0.8% for Type 1 and up to 2% for Type 2 while for major depressive disorder (MDD), prevalence rates stand between 6.4%. Additionally, in Chile lifetime prevalence for MMD is 9.2% and 2% for any bipolar disorder.

It has been extensively suggested by research that patients with mood conditions are considered a high risk group for cognitive impairment. Among those, mild cognitive impairment (MCI), is an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. It is considered a transitional-preclinical stage between healthy aging and dementia. Over time, various definitions have been proposed for MCI and its subtypes, but in general, it is characterized by a measurable decline in one or more cognitive domains, such as memory, attention, language, executive function, or visual skills, that exceeds what might be expected based on an individual's age and education background, but does not markedly impair the individual's independence in everyday activities; it is also characterized by concerns about these cognitive changes, either reported by the patient or an informant. While not all individuals with mild MCI will go on to develop dementia, evidence suggests that those with this condition are at a higher risk, with annual conversion rates ranging from 8% to 15% per year. This is why detecting and treating MCI represents a critical opportunity for early intervention and potentially preventing or delaying the onset of more severe neurodegenerative diseases. Dementia is a general term to describe a condition characterized for a group cognitive and behavioral symptoms, observed in several conditions. According to the National Institute on Aging-Alzheimer's Association, it can be defined as the decline from previous levels of functioning and performing in at least two of the following areas, that must interfere with the usual functioning: 1) the ability to acquire and remember new information, 2) reasoning and handling of complex tasks or poor judgment, 3) visuospatial abilities, 4) language functions and 5) personality, behavior, or comportment. Among all causes of dementia, Alzheimer Disease (AD) is the most common form, representing 60-70% of cases.

There is substantial body evidence indicating that major MDD and BD are closely linked to the development of mild cognitive impairment (MCI) and dementia. Research has shown that individuals with affective disorders are particularly vulnerable, exhibiting a markedly higher risk of developing dementia and other neurodegenerative conditions, compared to the general population. Specifically, the risk estimates for developing dementia range from 1.90 to 3.02 for MDD, and 2.36 to 5.58 for BD. Further, people suffering affective disorders have also a 2.5 times higher risk of developing dementia when compared to other medical conditions like osteoarthritis of diabetes. This increased risk is thought to be associated with factors such as the chronic nature of bipolar disorder, the impact of mood episodes on cognitive function, and the potential shared underlying pathophysiological mechanisms between the two conditions.

Another important clinical aspect with this high risk of MCI and dementia group is pertained with earlier presentation of cases when compared with the general population. The pathophysiology underlying cognitive decline in mood disorders involves neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired neuroplasticity, all of which overlap with mechanisms observed in neurodegenerative conditions such as MCI and Alzheimer's disease (AD).

Lithium Evidence as Cognitive Protector Agent Lithium has long been recognized as the gold standard treatment for bipolar disorder, and has also played a significant role as an adjunct therapy for major depressive disorder. In recent years, however, the scientific community has shown increasing interest in the potential therapeutic applications of lithium beyond its traditional use in the management of BD and MDD. One particularly promising area is the prevention of cognitive decline in affective disorders. A growing body of evidence has suggested that lithium may possess neuroprotective properties, which could be leveraged to address the pressing challenges of dementia, MCI and other neurodegenerative disorders like Parkinson disease among others.

Research conducted to determine the underlying mechanisms of the potential neuroprotective effects of lithium have shown a diversity of targets. Its neuroprotective potential may be attributed to its ability to modulate several key cellular pathways involved in the pathogenesis of neurodegenerative disorders. For instance, lithium has been shown to inhibit glycogen synthase kinase-3 (GSK-3), a kinase that plays a central role in the hyperphosphorylation of tau protein, a hallmark pathological feature of Alzheimer's disease. This inhibition of GSK-3 by lithium helps to reduce the accumulation of hyperphosphorylated tau, which is a major contributor to the formation of neurofibrillary tangles, one of the characteristic hallmarks of Alzheimer's disease pathology. Moreover, lithium has also been found to enhance the activity of brain-derived neurotrophic factor (BDNF), a crucial neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis - all of which are compromised in the context of neurodegenerative diseases. The increased availability of BDNF due to lithium treatment has been shown to promote neuronal health and resilience, thereby mitigating the progression of neurodegenerative processes. Additionally, lithium exerts anti-inflammatory and antioxidant effects, which have been linked to its neuroprotective properties. Moreover, it may also exert its neuroprotective effects by inducing increases in the levels of the anti-apoptotic factor Bcl-2, thereby suppressing neuronal death and promoting cell survival. This action of lithium to enhance Bcl-2 levels and inhibit apoptosis has been observed in various in vitro and in vivo models of neurodegenerative conditions, suggesting that it is a key mechanism through which lithium produces its neuroprotective properties. Additionally, lithium has been found to modulate oxidative stress pathways, mitochondrial function, and neuroinflammation - all of which are implicated in the etiology of neurodegenerative disorders. By targeting these multiple pathways, lithium exhibits a multifaceted approach to neuroprotection, which may contribute to its potential therapeutic utility in the prevention and management of dementia and related neurodegenerative conditions. Taken together, these findings suggest that lithium may hold significant promise as a therapeutic agent for the prevention and management of dementia and other neurodegenerative conditions.

Neurocognitive role of lithium the prevention of dementia in affective disorders.

Seminal clinical evidence coming from a cohort of patients with mood illnesses followed for more than twenty years was reported in 2007. It was observed that long-term treatment with lithium in these subjects was associated with lower prevalence of dementia compared to patients not receiving lithium treatment . Other case-control study found that the prevalence of Alzheimer's disease was significantly lower in elderly euthymic patients with bipolar disorder who were on chronic lithium therapy compared to those who were not.

One promising avenue of research is the use of lithium in preventing mild cognitive impairment (MCI) and dementia. Recent research suggests that 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.

This proposal aims to investigate the effect of lithium on cognitive function in individuals at risk of developing these conditions. It is intended to determine the potential benefits of lithium in mitigating the progression of cognitive decline. Additionally, this research will contribute to our understanding of the role of lithium in neuroprotection and its potential implications for public health interventions aimed at reducing the burden of neurodegenerative disorders.

The present study aims to build upon this existing evidence by examining the efficacy of lithium trace supplementation in preventing cognitive decline and dementia in a large, well-designed randomized controlled trial. Specifically, this study will randomize cognitively healthy patients with mood disorders or patients with preexisting MCI to receive either a low-dose lithium supplement (50 mg daily) or a placebo, with the primary outcome being the incidence MCI or worsening of the preexisting MCI

II. HYPOTHESIS General Patients with mood conditions exposed to trace lithium dosage will have a smaller incidence of MCI or less worsening of preexisting MCI compared with patients receiving placebo.

Specific A. Trace dosage of lithium (50 mg/day) will be efficacious in preventing newly diagnosed MCI or worsening in existing MCI, in patients with mood conditions compared with patients receiving placebo.

B. There will not be a differential rate of adverse events related to trace lithium dosage compared with placebo.

C. There will be clinical features that may predict the lithium response in the active arm.

III. GOALS

General 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.

Specific Goals:

For General Goal A

1. Determine the incidence rate of newly diagnosed MCI in the lithium and placebo groups.
2. Determine the incidence of worsening of already diagnosed MCI in the lithium and placebo groups
3. Compare the cognitive decline trajectories in time for both groups.
4. Measure cognitive function using standardized assessments over the study period.
5. Compare the progression of profiles of cognitive decline between the two groups.

For General Goal B:

1. Identify demographic and clinical predictors of a positive response to lithium.
2. Assess the impact of lithium on secondary outcomes like quality of life and functional impairment.
3. Monitor and document any adverse events associated with lithium treatment
4. Analyze the safety profile of trace lithium dosage.

Procedures In each of the mentioned psychiatric facilities, eligible subjects will be invited to participate in the study as part of their primary care psychiatry. In case of interest, they will be contacted by one of the study's researchers to confirm that the eligibility criteria are met. Those subjects who meet the inclusion criteria and do not meet the exclusion criteria at baseline assessment will be included in the trial. After giving consent, subjects will be invited to undergo the baseline assessment.

Randomization 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 (defined clinically as the presence of executive dysfunction, attentional impairments, and/or poor working or short-term memory). Equipoise randomization, as has been implemented in other RCTs, will be used to minimize risks by allowing subjects and/or clinicians to exclude one of the two treatment arms if past clinical history and/or patient preferences indicate an undue risk for side effects in one of the arms.

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: Lithium 50 mg oral tablets per day (trace doses).
• Control arm: placebo tablet.

Assessments In both groups, the assessments will be carried out at the baseline and subsequently every six months over the next four years by blind researchers. Research study investigators will base this diagnosis on interviews with the patient, caregivers, clinicians, and/or chart assessments.

Data Analysis The primary analysis (by full intention-to-treat) will be a survival analysis of time to either detection of MCI or worsening of MCI as defined for the primary outcome during the scheduled treatment period of patients allocated to lithium versus placebo. Time to first event (newly diagnosed MCI or worsening of an already existing one) during the scheduled follow-up will be compared between the two groups. Follow-up time will be censored at the last available assessment in patients who will be lost to follow-up without having an event. Time from randomization to event will be summarized by Kaplan-Meier curves, and compared with the log rank test. Hazard ratios (HRs) with 95% CIs will be calculated with Cox's regression to estimate size of the treatment effect. The proportional hazards assumption will be tested formally with analysis of Schoenfeld residuals. All analyses will be performed with STATA.

Sample Size And Power It is planed to enroll 250 subjects. Based on the magnitude of effect and variation observed in our pilot clinical experience, it is projected that a sample size of 250 subjects will achieve a power of 0.80. It has been reported an Odds Ratio (OR) of 0.2 over 5 years, starting from the third and fourth decades of life, with absolute rates of 22% in mood disorder patients versus 5% in non-mood disorder controls. The mean age was 68. Based on these findings, an estimated Hazard Ratio (HR) of 0.7 for our overall sample of 250 subjects is expected.

Inclusion Criteria:

1. Age 55-70.
2. DSM-5 diagnosis of major depressive disorder or bipolar disorder (types I or II), current or lifetime.
3. Prior to participation in this study, each subject must sign an informed consent.

Exclusion Criteria:

1. Current mood treatment with lithium.
2. Alcohol dependency within the past month.
3. Current serious unstable medical conditions or history of medical illness that would contraindicate a trial of lithium.
4. Current or past severe kidney disease or baseline creatinine > 1.5 mg/dl.
5. Active suicidal ideation with plan and intent (Columbia Suicide Severity Rating Scale Screen Version (C-SSRS Screen) > 3 points).
6. Current or past severe thyroid disease or baseline TSH >5.0 uUI/dl.
7. Current diagnosis of dementia of any kind.