Lithium Effects on the Brain's Functional and Structural Connectome in the Treatment of Bipolar Disorder

Lithium is highly effective in the treatment of bipolar disorder. This study aims to investigate, for the first time, the impact of lithium monotherapy on the structural and functional connectivity of the brain using MRI imaging.

Study Overview

• Status: Active, not recruiting
• Conditions: Depression; Bipolar Disorder; Bipolar Depression; Major Depressive Episode; Bipolar I Depression; Bipolar II Depression
• Intervention / Treatment: Drug: Lithium

Detailed Description

The premise of this proposal is that the clinical efficacy of lithium in bipolar disorder, and its complex effects on multiple brain physiological functions, may be best deciphered using a network properties-metric approach. This approach is critical because it provides insight into the function of brain networks (e.g., resilience to disruption, central hubs), which is likely to be more closely linked to behavioral outcomes. Furthermore, we will conduct an exploratory investigation of the in vivo molecular effects of lithium by measuring peripheral gene expression. To bring these together, we will also explore whether connectome changes serve as mediator between molecular changes (i.e., gene expression) induced by lithium treatment and behavioral changes (e.g., depression, mood stability, suicidality).

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation Center for Behavioral Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Bipolar disorder and healthy controls

Description

Inclusion criteria for BD subjects:

• ages 18-60 years (inclusive) and able to give voluntary informed consent;
• Satisfy criteria for Diagnostic and Statistical Manual 5th edition (DSM-V) for BD I or II, current Depressive Episode;
• 17-item Hamilton Depression Rating Scale (HAM-D) score >15 and <25;
• Young Mania Rating Scale (YMRS) < 8;
• no psychotropics in the last 2 weeks (if previously on fluoxetine then medication free for 5 weeks) OR on stable psychotropic medications for 12 weeks
• no lithium treatment for past 6 months;
• satisfy criteria to undergo an MRI scan based on MRI screening questionnaire;
• able to be managed as outpatients during the study as ascertained by Clinical Global Severity Scale < 5 (i.e., moderately ill) and no significant suicidal or homicidal ideation or gross disability.

Exclusion criteria for BD subjects are:

• meeting DSM-IV criteria for schizophrenia, schizoaffective disorder, or an anxiety disorder as
• a primary diagnosis;
• requiring inpatient treatment;
• meeting DSM-V criteria for substance dependence within the past 3 months, except caffeine or nicotine;
• positive urinary toxicology screening at screening visit;
• use of alcohol in the past 1 week;
• serious medical or neurological illness;
• current pregnancy or breast feeding;
• metallic implants or other contraindications to MRI.

Inclusion criteria for healthy subjects:

• ages 18-60 years and ability to give voluntary informed consent;
• no history of psychiatric illness or substance abuse or dependence;
• no significant family history of psychiatric or neurological illness in first degree relative;
• not currently taking any prescription or centrally acting medications;
• no use of alcohol in the past 1 week;
• and no serious medical or neurological illness.

Exclusion criteria for healthy subjects are:

• under 18 years of age;
• pregnant or breast-feeding;
• metallic implants or other contraindication to MRI.

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Bipolar Disorder I or II Depressed; DSM-V Bipolar I or II Depressed treated with lithium	Drug: Lithium; Open-label lithium treatment for Bipolar Disorder Subjects Healthy Controls only repeat testing - no intervention; Other Names: Lithium carbonate or citrate or Lithium extended release
Healthy Controls; Healthy Controls with no psychiatric history

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Connectivity (Fc) changes	Investigate effects of lithium monotherapy treatment of BD on changes in Fc through fMRI imaging from baseline after 2, 8, and 26 weeks of treatment and test whether these changes correlate with improvement in state-related symptoms and longer term mood stability. Healthy controls will also be scanned at the same time points but not treated.	2, 8, 26 weeks
Structural Connectivity (Sc) changes	Investigate effects of lithium monotherapy treatment of BD depression on changes in the diffusion weighted imaging Sc through fMRI imaging from baseline after 2, 8, and 26 weeks and test whether these changes correlate with depression severity and mood stability. Healthy controls will also be scanned at the same time points but not treated.	2, 8, 26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in peripheral gene expression	An exploratory investigation of whether lithium-related changes in the functional and structural connectome over time represent a link between shifts in peripheral gene expression and improvement in illness-related measures.Lithium therapy will be associated with changes in gene expression pathways such as the mitochondrial-carnitine shuttle pathway, which in turn will be related to changes in the functional and structural connectome.	2, 8, 26 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Amit Anand, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Actual): June 30, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: October 5, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Depression; Bipolar Disorder; Lithium; Bipolar I and II Depression
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Mental Disorders; Behavioral Symptoms; Mood Disorders; Behavior; Depression; Bipolar Disorder; Organic Chemicals; Acids, Acyclic; Carboxylic Acids; Inorganic Chemicals; Metals, Alkali; Elements; Metals, Light; Metals; Alkalies; Carbon Compounds, Inorganic; Citrates; Tricarboxylic Acids; Carbonates; Carbonic Acid; Lithium Compounds; Lithium Carbonate; Citric Acid; Lithium
• Other Study ID Numbers: 17-441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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