Cognitive Dysfunction and Glucagon-like Peptide-1 Agonists
Condition: Bipolar Disorder; Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major; Bipolar Disorder; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 3

Summary: 
      Cognitive deficits are a core feature across disparate brain disorders, being highly
      prevalent and pervasive. Impairments in executive function are one of the most consistent
      findings in clinical and meta-analytical studies and were reported to be a principal mediator
      of psychosocial impairment and disability. Cognitive dysfunction is thought to be underlied
      by abnormalities in distributed brain circuits, at the cellular and molecular levels.
      Nonetheless, the neural mechanisms underlying the dysregulation in these circuits are poorly
      understood. Emerging evidence indicates that metabolic abnormalities are highly relevant for
      the domain of cognitive function and indicate that alterations in metabolic pathways may be
      relevant to neurocognitive decline across different populations. The incretin glucagon-like
      peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors are
      widely expressed in the central nervous systems. Pre-clinical trials have demonstrated
      significant neuroprotective effects of GLP-1. Ongoing clinical trials measuring cognition and
      mood in populations with various psychiatric disorders lend further impetus to explore the
      effects of GLP-1R agonists on brain structure and cognitive function. We hypothesize that
      GLP-1 and the GLP-1R are relevant for molecular and cellular processes that are thought to
      underlie the formation and maintenance of brain circuits. A derivative of this hypothesis is
      that the administration of GLP-1 agonists may result in enhanced neuronal survival and
      consequential increase in gray matter volume. We therefore propose to explore the cellular
      and molecular abnormalities within and between neural circuits subserving cognition using the
      GLP-1R agonist liraglutide.

      The overall goal of this study is to explore the relationship between a metabolic molecular
      target (i.e. the GLP1 system), the neural circuits of interest and the behavioral phenotype
      cognitive function.
    

Detailed description: 
      We propose to explore the effects of GLP-1 agonism on brain structure and function. We
      hypothesize that the administration of GLP-1 agonists may result in increased connectivity in
      the executive control network. Multiple clinical trials with pharmacological agents, as well
      as cognitive therapy, have reported that measurements of brain structure and function are
      correlated with cognitive performance, indicating that they are a valid biological correlate
      of cognitive function. To assess this hypothesis we will recruit a clinical population,
      represented by individuals with a measurable impairment in executive function, wherein the
      target of our proposed intervention was shown to be altered.

      We are currently not in a position to sufficiently homogenize subgroups of adults with mood
      disorder on the basis of any single or combinatorial biomarkers. It is also unlikely that
      alterations in GLP-1 receptor function, and the proposed model herein, is sufficiently
      explanatory to all sub-populations of adults with mood disorders. Instead, we propose that
      adults with mood disorders, who have co-existing metabolic disorders (e.g. type 2 diabetes
      mellitus), would be more likely to have a brain illness that is influenced by (i.e. cause,
      consequence or both) alterations in cellular bioenergetics. Moreover, convergent evidence
      suggest that GLP-1 receptor function may be, at least partially, dependent on glucose levels
      and/or insulin sensibility. It is a separate, yet testable, hypothesis that subpopulations
      enriched on the basis of having metabolic comorbidity (i.e. insulin resistance) may be more
      responsive to an intervention that targets a metabolic pathway.

      We plan to test the effects of adjunctive liraglutide on executive function. We will select a
      subpopulation of patients, with a mood disorder and impairment in executive function, as
      defined by a below-average (i.e. 1 standard deviation below norm) performance in the Trail
      Making Test-B (TMTB). Furthermore, we plan to recruit two groups of patients, with and
      without insulin resistance, as defined by a homeostatic model assessment for insulin
      resistance (HOMA-IR) above 2.5, which will allow a comparison of the effects of liraglutide
      in a metabolically heterogeneous population.
    

Intervention name(s): Liraglutide
Intervention type(s): Biological
Intervention description(s): Study participants will received the following study intervention in addition to 'standard of care' treatment: Adjunctive liraglutide will be initiated at 0.6 mg for the first 1 week, then increased to 1.2 mg with the option of increasing to 1.8 mg thereafter based on efficacy/tolerability (n=15 in each group). Liraglutide will be adjunctively administered to a conventional antidepressant, antipsychotic and mood stabilizing agent at guideline-concordant therapeutic plasma levels. Subjects will be randomized to receive liraglutide for a 4 week period. No major change in the pharmacological regimen will be permitted during the 4 week trial unless required for medical reasons.
Intervention MeSH terms: Liraglutide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment