Brain Insulin Resistance in Mood Disorders

The overarching aim of the study is to determine the role of insulin signaling on the neurobiological substrates subserving anhedonia within individuals with mood disorders (i.e., Bipolar Disorder (BD) and Major Depressive Disorder (MDD)).

Specific aims include:

1. Molecular: Assessment of components of the insulin cascade, as well as of anhedonia and reward-related processes, using a proteomics and gene expression approach;
2. Physiology: Measurement of peripheral sensitivity to insulin and metabolic correlates, including body mass index and dyslipidemia;
3. Neural Circuits: Evaluation of the insulin sensitivity of prefrontal (e.g. prefrontal cortex) and striatal (e.g. nucleus accumbens, ventral tegmental area) networks in the resting-state and during an effort-based decision making test, using acutely administered intranasal insulin and functional magnetic resonance imaging (fMRI);
4. Behavioral: Measurement of willingness to make effort for rewards, as well as of other components of reward response and anhedonia, using validated behavioral tasks and clinical scales (e.g. Snaith-Hamilton Pleasure Scale - SHPS).

This initiative represents a proof-of-concept study that insulin is important to anhedonia, neurocognitive functioning, and behavioural deficits in MDD, representing a novel and safe therapeutic avenue.

Seventy-five adults between the ages of 18 to 50 years with DSM-5 defined MDD or BDI/II, in a depressive episode will be enrolled, in addition to seventy-five age- and sex-matched healthy controls. 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 and BD will be permitted.

Participants will be excluded if they are receiving insulin and/or oral hypoglycemiants; have been diagnosed with possible or probable Alzheimer's Disease, Mild Cognitive Impairment, or any other dementia; have a history of neurological disorder, or evidence of neurologic or other physical illness that could produce cognitive deterioration; have substance use disorder within 3 months before screening or a positive baseline toxicology screen; have a clinically unstable general medical illness; are pregnant or breastfeeding; have MRI contraindications.

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 3 visits: one screening visit and two fMRI scan visits.

Screening and Baseline Assessment: Subjects will first meet with a staff psychiatrist for a clinical consultation. After obtaining consent and if inclusion criteria are met, a medical comorbidity questionnaire will be administered to screen for concurrent and lifetime medical conditions. Participant's demographic characteristics and current medications, as well as lifetime psychotropic medications received will be recorded. The investigators will also assess dietary intake with the short food frequency questionnaire (SFFQ); smoking, by questioning number of cigarettes smoked per day, age when smoking stated, and quit date, if applicable, to calculate a smoking pack-year history; physical activity using the International Physical Activity Questionnaire (IPAQ); and alcohol and/or substance abuse with the Addiction Severity Index (ASI). In addition, the investigators will assess demographics, socioeconomic status, medical history, and family psychiatric history; childhood trauma history with the Childhood Trauma Questionnaire (CTQ) will also be assessed. Participants will also be asked to complete an MRI screening questionnaire to ensure that they have no contraindications. The following self-reported measures will be carried out: Perceived Deficits Questionnaire-Depression (PDQ-D), Sheehan Disability Scale (SDS), UCLA life Stress (Episodic), DeJong Gierveld Loneliness Scale, Pittsburg Sleep Quality Index (PSQI), Social and Occupational Functioning Assessment Scale (SOFAS). Participants will be required to complete a urine drug screen. Female participants will be asked to do blood work to confirm they are not pregnant.

Physiological Assessment: Anthropometric (i.e. BMI, waist-hip ratio) and metabolic measurements (i.e. fasting glucose, fasting insulin, glycated hemoglobin, lipids and HOMA-IR) will be completed at each study visit.

Behavioral assessment: These tasks are simple, user-friendly tools that provide an opportunity, when used in conjunction with the most widely used questionnaires, to gain novel insights on reward behaviors in mood disorders.

1. The primary behavioral measurement will be effort-based decision-making, assessed using the Effort-Expenditure for Rewards Task (EEfRT), which will be done in a fMRI paradigm.
2. Assessments will include the validated anhedonia scale Snaith-Hamilton Pleasure Scale (SHPS), and the mood questionnaires Montgomery-Åsberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) during each study visit.

Neural Circuits Assessment: A promising tool to study the effect of insulin on CNS is intranasal insulin, which is delivered directly into the brain, without relevant effects on peripheral glucose. A single dose of intranasal insulin has been shown to influence brain activation, increasing regional perfusion and functional connectivity between the hippocampus and the PFC. Acute administration of intranasal in randomized, placebo-controlled, cross-over designs has been previously used to determine regional responses to insulin in the resting-state or during tasks.

After screening and baseline assessment, participants will receive a crossover treatment assignment of either insulin or diluent followed by an MRI scan, with a washout period of 1 week. Therefore, participants will receive a total of 2 MRI scans throughout the course of the study- one following the first treatment, and one following the second treatment. The subsample will be enriched for the presence of self-reported anhedonia, using a score of greater than 2 on the SHPS as a cut-off, which provides the best discrimination between "normal" and "abnormal" level of hedonic tone. This subsample will also have equal representation of normal weight and obese participants. Imaging procedures will be done in collaboration with the Centre for Addiction and Mental Health (CAMH). CAMH is Canada's largest mental health teaching hospital and one of the world's leading research centres in its field. CAMH is fully affiliated with the University of Toronto and is a Pan American Health Organization/World Health Organization Collaborating Centre.

To proxy insulin activity within pre-selected brain regions, the investigators will use a provocation paradigm, involving the administration of exogenous intranasal insulin, based on the published work of other research groups. Activation of brain regions will be assessed during the resting state and task-based reward paradigm (i.e. EEfRT), following an intranasal administration of either 160 units of intranasal insulin or diluent (insulin and placebo will be prepared as nasal sprays), in a randomized, double-blinded, cross-over design. A hypothesis-driven region of interest approach will be used to investigate initially the striatum and the medial PFC (mPFC). Willingness to make effort for rewards will be measured with the EEfRT.

Imaging procedures will be started with a safety monitoring for glucose and cardiovascular vital signs. An insulin/placebo spray will be administered intranasally and, within 30 min, fMRI measurement will be performed. Venous blood samples, for determination of plasma glucose and insulin concentrations, will be obtained at the time of the insulin/placebo spray administration and immediately after the scan. The 2 scans for each individuals will be acquired on the same scanner. Subjects will be scanned using a 3.0-Tesla Signa HDx scanner with an 8-channel phased-array receiver coil (GE Healthcare, Milwaukee, Wisconsin) consisting of a structural and functional neuroimaging, comprising:

1. Whole-brain 3-D T1-weighted Inversion-Recovery prepared Fast Spoiled Gradient-Echo (IR-FSPGR) anatomical scan with the following parameters: (TI/TR/TE = 450/8/3 ms, matrix size 256 × 256, field of view 22 × 22 cm, slice thickness = 1 mm, and flip angle = 15°)
2. Whole-brain, T2\*-weighted BOLD echo planar imaging (EPI) during awake resting state with the following parameters: (TR/TE = 2000/30 ms, 3.5 x 3.5 x 3.5 mm voxel size, field of view 24x24 cm, 39 slices, slice thickness 3.5 mm, matrix size 64x64, number of frames = 405, flip angle = 70°)),
3. Three runs of whole-brain, T2\*-weighted BOLD EPI series during task-based reward paradigm with the same parameters as in ii.

Eligibility Criteria:
Inclusion criteria (patients):

1. Age 18-60
2. DSM-5 defined MDD/BD and a total score ≥20 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and no history of dementia or intellectual disability
3. A written, voluntary informed consent prior to study enrollment

Exclusion criteria (patients):

1. Use of insulin and/or oral hypoglycemiants, due to its confounding effects
2. Diagnosis of possible or probable AD, MCI, or any other dementia
3. History of neurological disorder, or evidence of neurologic or other physical illness that could produce cognitive deterioration
4. Substance use disorder within 3 months before screening or a positive baseline toxicology screen
5. Presence of clinically unstable general medical illness
6. Pregnancy or breastfeeding
7. MRI contraindications

Inclusion criteria (healthy controls):

1. Age 18-60
2. A written, voluntary informed consent prior to study enrollment

Exclusion criteria (healthy controls):

1. Use of insulin and/or oral hypoglycemiants, due to its confounding effects
2. Presence of any current or lifetime psychiatric or neurological conditions
3. Substance use disorder within 3 months before screening or a positive baseline toxicology screen
4. Presence of clinically unstable general medical illness
5. Pregnancy or breastfeeding
6. MRI contraindications