The Effect of Intranasal Insulin on Neurocognitive Function in Euthymic Patients With Major Depressive Disorder

It is hypothesized that intranasal administration of insulin will enhance hippocampal-dependent neurocognitive performance in euthymic individuals with major depressive disorder. This novel initiative represents a proof-of-concept study that insulin is salient to neurocognitive functioning in major depressive disorder; it also represents a novel and safe therapeutic avenue. The available literature suggests that the acute administration of intranasal insulin enhances cognition in memory-impaired older adults with either Alzheimer's disease or minimal cognitive impairment. Prior research demonstrates a cognitive enhancing effect of insulin within one hour of the first intranasal insulin dose. Other studies suggest that the long-term administration of intranasal insulin (i.e. over eight weeks) enhances memory performance in human volunteers. We aim to evaluate the acute and long-term effects of intranasal insulin administration in persons with major depressive disorder. As such, the neuropsychological testings will be conducted at three time points: the week before receiving insulin, within one hour of the first dose and after eight weeks of insulin administration.

Ninety subjects between the ages of 18 and 60 with DSM-IV-TR defined MDD (diagnosis will be confirmed by the Mini International Neuropsychiatric Interview for the DSM-IV) will be enrolled. Individuals below the age of 18 and over 60 are excluded as they are not seen at the two recruiting centers. Enrolment into the study is voluntary. Eligible subjects will provide written informed consent. Subjects will be enrolled from the outpatient Mood Disorder Psychopharmacology Unit (MDPU), University Health Network, University of Toronto and the Mood Disorders Program at McMaster University. Study information and consent procedures will be provided by personnel other than the primary treatment provider.

Euthymia (the absence of clinically meaningful symptoms) will be prospectively defined as a score of 7 or less with the Hamilton Rating Scale for Depression 17 item (HAMD-17) at initial assessment and at 1 month (baseline). Subjects should have a score of at least 1 SD below norm matched for age and sex in the Hopkins Verbal Learning Test-Revised Version (HVLT-R) to meet inclusion criteria. This criterion is added as a method of sample enrichment. The MDPU case report form will gather information on subject course of illness variables. Conventional pharmacological treatments for major depressive disorder 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.

Subjects 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. Individuals with diabetes mellitus will be excluded as diabetes is independently associated with neurocognitive deficits. Other exclusion criterion includes the inability to provide written informed consent. The HAMD-17 will be administered at baseline and weekly throughout the 8-weeks of treatment assignment. Any subject experiencing a mood event (HAMD17 > 7 on two consecutive visits) will be excluded. Subjects who are actively suicidal or evaluated as being a suicide risk will also be excluded. Other reasons for discontinuation are voluntary discontinuation, failure to complete 1 month of euthymia, impaired fasting glucose (i.e. 6.1-6.9 mmol/L), non-compliance (i.e. failure to administer > 80 % of the assigned treatment in any week). Insulin will be measured quantitatively on a weekly basis; subjects will also complete a diary of when they took intranasal insulin and their prescribed medication.

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 subject's primary care provider in regards to their participation in this study.

This is a randomized double-blind, placebo-controlled, parallel-group study.

The initial visit entails the provision of detailed study information to a subject and obtainment of written informed consent from the subject. The subject will then meet a research team member at a later date for a screening visit. This study requires a total of 12 visits.

Neuropsychological testing will be conducted at 3 time points:

1. Baseline (Visit 3)
2. Within 60 minutes of the first administration of randomized treatment (Visit 4)
3. Endpoint (Visit 12)

• Drug: Diluent
  Intranasal spray; 8 weeks
• Drug: Intranasal Insulin
  Intranasal spray; 40 IU qid; 8 weeks

• Active Comparator: 1
  Intervention: Drug: Intranasal Insulin
• Placebo Comparator: 2
  Intervention: Drug: Diluent

Inclusion Criteria:

• Major Depressive Disorder - Euthymic

Exclusion Criteria:

• Unstable medical conditions