Cognitive Dysfunction and Glucagon-like Peptide-1 Agonists

NCT02423824 | Completed Phase 3

• 1 other identifier: 14-8561-A
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Bipolar Disorder; Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Executive function

  The primary efficacy variable will be mean change from baseline to week 4 on executive function performance, as measured by Trail Making Test B.

  4 weeks

Secondary Outcomes (1)

• Resting-state functional network connectivity

  4 weeks

Study Arms (2)

Insulin Resistance

ACTIVE COMPARATOR

Adjunctive Liraglutide 1.2-1.8mg/day

Biological: Liraglutide

Non-Insulin Resistance

ACTIVE COMPARATOR

Adjunctive Liraglutide 1.2-1.8mg/day

Biological: Liraglutide

Interventions

Liraglutide BIOLOGICAL

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.

Insulin Resistance; Non-Insulin Resistance

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Informed consent before study-related activity
• Individuals between the ages of 18 and 45 who meet DSM-5 criteria for bipolar disorders or depressive disorders
• Below-average (i.e. 1 standard deviation below norm) performance in the TMTB.
• Individuals must be receiving guideline concordant pharmacotherapy, in stable doses, without withdrawal or addition of medication in the last month.

You may not qualify if:

• Diagnosis of possible or probable AD, MCI, or any other dementia
• History of neurological disorder (ischemic attacks, carotid bruits, or lacunes upon MRI scan), or evidence of neurologic or other physical illness that could produce cognitive deterioration
• Individuals in a severe mood episode, defined as a Hamilton Depression Rating scale 17- item (HAMD-17) total score of \>23 or a Young Mania Rating Scale (YMRS) total score of \>20.
• Actively suicidal or evaluated as being a suicide risk (operationalized as a score of ≥3 on HAMD-17 suicide item and/or by clinical assessment).
• Substance use disorder within 3 months before screening or a positive baseline toxicology screen.
• Currently being treated for diabetes, with oral hypoglycemic agents and/or insulin, as these medications affect glucose and insulin levels, as well as the HOMA-IR calculation.
• Presence of absolute or relative contraindication to liraglutide (e.g. hepatic impairment, renal impairment with CKD stage 3 and above, personal or familial history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2)
• History of alcoholism; history of pancreatitis or pancreatic cancer
• Presence of clinically unstable general medical illness.
• Pregnancy or breastfeeding women.

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Mood Disorders Psychopharmacology Unit

Toronto, Ontario, M5T 2S8, Canada

Location

MeSH Terms

Conditions

Bipolar Disorder; Depressive Disorder, Major

Interventions

Liraglutide

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders; Depressive Disorder

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Roger S McIntyre, M.D.

  Professor of Psychiatry and Pharmacology, University of Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2015
• First Posted: April 22, 2015
• Study Start: May 1, 2015
• Primary Completion: April 1, 2016
• Study Completion: May 1, 2016
• Last Updated: May 13, 2016

Record last verified: 2016-05

Locations

CA (1)