Effect of Intranasal Insulin on Depressive Symptoms in Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 3

Summary: 
      The primary aim of the study is to determine whether adjunctive intranasal insulin will exert
      an antidepressant effect when compared to placebo in adults with major depressive disorder
      (MDD), insufficiently responsive conventional antidepressants. There are three secondary aims
      of the study (1) to determine whether adjunctive intranasal insulin will alter emotional
      processing (i.e., cognitive-affective interface); (2) to determine whether early changes in
      emotional processing (i.e., after a single dose at 40IU intranasal insulin) predicts
      symptomatic improvement at study endpoint; and (3) to determine the effect of intranasal
      insulin on neurocognitive performance (e.g., learning and memory). This initiative represents
      a proof-of-concept study that insulin is important to depressive symptoms, neurocognitive
      functioning, and emotional processing deficits in MDD, representing a novel and safe
      therapeutic avenue.
    

Detailed description: 
      Emerging evidence for impairments at the cognitive-affective interface, frequently defined as
      affective cognition, are increasingly being recognized as a core feature of mood disorders,
      particularly MDD. Individuals with MDD consistently exhibit abnormalities in verbal memory
      with particular difficulty in memory tasks such as list learning and free recall. The
      administration of intranasal insulin has been reported to improve verbal memory, declarative
      memory in individuals with Alzheimer's disease or Mild Cognitive Impairment as well as
      measures of mood (e.g., overall feeling of well-being, self-esteem, and depression) in
      healthy volunteers. The effect of intranasal insulin on any measure of neurocognitive
      function and emotional processing in MDD is currently unknown.

      Thirty participants between the ages of 18 and 60 with DSM-IV-TR defined MDD [confirmed by
      the Mini International Neuropsychiatric Interview (MINI)] will be enrolled. Individuals below
      the age of 18 and over 60 are excluded as they are not seen at the recruiting center.
      Enrollment into the study is voluntary. Eligible participants will provide written informed
      consent. Participants will be enrolled from the outpatient Mood Disorders Psychopharmacology
      Unit (MDPU), University Health Network (UHN), University of Toronto.

      The MDPU case report form will gather information on the participant's course of illness
      variables. Conventional pharmacological treatments for MDD will be permitted (e.g.,
      conventional antidepressants). Conventional unimodal antidepressants modulate cerebral
      glucose metabolism; as such, they will be kept consistent throughout the duration of the
      study and will not be altered from the point of randomization to study endpoint.
      Antidepressants and augmentation strategies with significant anti-cholinergic potential
      (e.g., paroxetine, tricyclic antidepressants) as well as benzodiazepines will be exclusionary
      as they may negatively affect neurocognitive function.

      Participants will be excluded if they are receiving corticosteroids or antihypertensive
      medications; misused substance or alcohol in the past 3 months; received electroconvulsive
      therapy in the last 1 year; or have a neurological or medically unstable condition. Another
      exclusion criterion includes the inability to provide written informed consent. The
      Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale
      17-Item (HAM-D-17) will be administered at baseline and weekly throughout the 8 weeks of
      treatment assignment. Participants who are actively suicidal or evaluated as being a suicide
      risk will also be excluded. Other reasons for discontinuation are impaired fasting glucose
      (i.e., 6.1 - 6.9 mmol/L), and non-compliance (i.e., failure to administer ≥ 80% of the
      assigned treatment in any week).

      The ongoing provision of care is not contingent on enrollment and/or completion of the study
      protocol. Furthermore, there will be ongoing communication with the participant's primary
      care provider in regards to their participation in this study.

      This is a randomized double-blind, placebo-controlled, cross-over study. The initial visit
      entails the provision of detailed study information to the patient and obtainment of written
      informed consent from the participant. The participant will then meet a research team member
      at a later date for a screening visit. This study requires a total of 12 visits.

      Full neuropsychological testing will be conducted at 4 time points:

        1. Baseline1 (Visit 3)

        2. Endpoint1 (Visit 7)

        3. Baseline2 (Visit 8)

        4. Endpoint2 (Visit 12)
    

Intervention name(s): Diluent / Insulin; Insulin / Diluent
Intervention type(s): Drug; Drug
Intervention description(s): Diluent (4 Weeks ) / Intranasal insulin (4 weeks); Intranasal Insulin (4 Weeks ) / Diluent (4 Weeks)
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Major Depressive Disorder, Memory, Executive function