The Neurotrophic Effects of Lithium Carbonate Following Stroke: A Feasibility Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2014 by Sunnybrook Health Sciences Centre
Sponsor:
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier:
NCT01112813
First received: April 27, 2010
Last updated: December 19, 2014
Last verified: December 2014
  Purpose

Stroke is the leading cause of adult disability and the third leading cause of death in Canada. Most stroke survivors live with residual impairments that diminish independence and quality of life. This may include vascular cognitive impairment (loss of ability to plan, think and reason) which can lead to dementia and loss of mental and functional independence.

The current treatment to reduce stroke induced brain tissue injury is limited to thrombolytics (clot busters), a therapy useful only if given in the first hours following stroke. One major new approach aims to reduce cell death after stroke by targeting the ongoing tissue loss initiated by the stroke. The tissue can be maintained by interfering with later neurochemical processes that are activated by stroke, potentially through activating natural substances in the brain that help survival and growth of nerve cells ("neurotrophic" factors).

The recent recognition of lithium as a neurotrophic agent has generated the first studies of lithium treatment for managing brain diseases. Clinically, lithium has now been shown to increase brain gray matter volume in bipolar patients. This effect is potentially important in stroke because gray matter loss has been implicated in the development of cognitive impairment after stroke, a result of the series of brain processes that are activated by lack of oxygen due to stroke. Our primary objective is to examine the effects of lithium on total brain gray matter volume in the post-stroke population, as measured by volumetric magnetic resonance imaging (MRI) with the hope that lithium may increase gray matter volume in post-stroke patients and lead to greater cognitive and functional rehabilitation. This study will provide valuable information on the tolerability of lithium, and its effects on clinical outcomes relevant to stroke, providing the information needed for designing a large-scale clinical trial.


Condition Intervention Phase
Stroke
Drug: Lithium Carbonate
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Neurotrophic Effects of Lithium Carbonate Following Stroke: A Feasibility Study

Resource links provided by NLM:


Further study details as provided by Sunnybrook Health Sciences Centre:

Primary Outcome Measures:
  • Increase in total brain gray matter volumes [ Time Frame: Baseline, 2 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Cognitive tasks of the Neurological Disorders and Stroke - Canadian Stroke Network's (NINDS-CSN) 30 min. battery [ Time Frame: Baseline, 2 months ] [ Designated as safety issue: No ]
  • Serum brain-derived neurotrophic factor (BDNF) levels [ Time Frame: Baseline, 2 months ] [ Designated as safety issue: No ]
  • Serum lithium and creatinine levels [ Time Frame: 1-week, 4-weeks, 8-weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 35
Study Start Date: April 2010
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lithium
Lithium Carbonate, 0.4-0.8 mmol/L for 2 months
Drug: Lithium Carbonate
0.4-0.8 mmol/L for 2 months
Other Name: Carbolith

Detailed Description:

The recognition of lithium as a neurotrophic agent has provided a rationale for evaluation of this agent in animal models of cerebral ischemia. Numerous animal and in vitro studies have shown lithium-mediated neurotrophic effects involve mechanisms highly relevant to the post-stroke population: the induction of brain-derived neurotrophic factor (BDNF) and inhibition of abnormal activity of glycogen synthase kinase 3 (GSK-3). Lithium has consistently been shown to increase serum concentration of the neurotrophic factor, BDNF. BDNF is involved with neuronal proliferation, survival, and differentiation and it facilitates cortical reorganization and functional recovery after focal ischemia (in rats). GSK-3 is a neurotrophic intermediary. In animal and in vitro models, lithium treatment effectively reduces the severity of ischemic damage and protects against ischemic damage of central nervous system (CNS) neurons resulting from glutamate-induced cell death. Importantly, these benefits were present when lithium was given after ischemic events rather than prophylactically.

The goal of pharmacotherapy post-stroke is to enhance restoration of neurological function and limit structural degradation. Gray matter atrophy is a relevant post-stroke relevant outcome as it has been implicated in the development of vascular cognitive impairment after stroke and is a result of the series of neurochemical processes that are activated by ischemia. While the first clinical studies examining the neurotrophic effects of lithium and its effects on total gray matter volume in bipolar subjects have just emerged, this has yet to be explored in the post-stroke population. Our primary objective is to determine the tolerability of lithium following a stroke and to examine its effects on clinical outcomes including total brain gray matter volume as measured by volumetric magnetic resonance imaging (MRI).

In this feasibility study, lithium carbonate (target 0.4 to 0.8 mmol/L) will be given open-label for 60 days, to consenting patients with unilateral ischemic cortical lesions. Total gray matter volume using magnetic resonance imaging will also be measured at baseline and termination, and related to changes in clinical outcomes (standardized scales measuring cognitive, activities of daily living, motor recovery) performed at the time of the MRIs. We expect to find that post-stroke patients receiving lithium will have increases in gray matter volume, and that increase in gray matter volume will predict improvements in clinical outcomes over 60 days. In addition, since lithium has been shown to increase serum concentration of the neurotrophic factor, BDNF, we will explore the relationship between plasma BDNF concentrations and neurological and clinical outcomes.

This study will provide key information of clinical importance that will determine whether a clinical trial with lithium is desirable and feasible. Results of this project have the potential to focus the development of lithium as a new treatment strategy that would improve outcomes at both the individual and societal level.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age >40 years
  • male or female
  • speaks and understands English
  • within 12 months post-stroke

Exclusion Criteria:

  • subarachnoid or intracranial hemorrhage
  • severe aphasia or dysphasia
  • impaired level of consciousness that would preclude neuropsychiatric testing
  • significant acute medical illness that may contraindicate lithium treatment(including renal dysfunction; >106 umol/L creatinine level) affect neuropsychiatric assessments or serum BDNF results or put subject at risk from MRI procedure
  • other psychiatric (exception of post-stroke depression) or neurological illnesses
  • initiation of diuretic treatment
  • use of antidepressant medications or initiation of antidepressant medications during the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01112813

Contacts
Contact: Romeo A Penheiro, BSc 416-480-6100 ext 3185 rpenheir@sri.utoronto.ca
Contact: Maisha M Khan, BSc 416-480-6100 ext 3185 mkhan@sri.utoronto.ca

Locations
Canada, Ontario
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M5M1P3
Contact: Romeo A Penheiro, BSc    416-480-6100 ext 3185    rpenheir@sri.utoronto.ca   
Principal Investigator: Krista L Lanctôt, PhD         
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
Principal Investigator: Krista L Lanctôt, PhD Sunnybrook Health Sciences Centre
Principal Investigator: Nathan Herrmann, MD Sunnybrook Health Sciences Centre
  More Information

No publications provided

Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT01112813     History of Changes
Other Study ID Numbers: Li-2010
Study First Received: April 27, 2010
Last Updated: December 19, 2014
Health Authority: Canada: Ethics Review Committee

Keywords provided by Sunnybrook Health Sciences Centre:
Stroke
lithium
MRI
gray matter

Additional relevant MeSH terms:
Stroke
Brain Diseases
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Nervous System Diseases
Vascular Diseases
Lithium
Lithium Carbonate
Antidepressive Agents
Antimanic Agents
Antipsychotic Agents
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on August 03, 2015