Characterizing Synaptic Density in Treatment Resistant Depression

Unity Health Toronto45 enrolled

Overview

The purpose of this study is to better understand how certain brain systems work in people with depression, especially in those whose symptoms have not improved with antidepressant treatments. The investigators are particularly interested in synaptic density, which helps to understand how different parts of the brain communicate with one another. Synaptic density levels have implications on overall brain function and cognition. By comparing brain function in people with treatment-resistant depression, people with treatment-responsive depression, and healthy controls, investigators hope to better understand why some individuals do not respond to antidepressants. This research may help guide the development of more effective treatments in the future.

This research project examines synaptic density in the brain. Synaptic density refers to the number of communication connections that exist between brain cells in a given area, which provides researchers with information about how efficiently brain regions communicate. Researchers are studying synaptic density to better understand how brain communication may differ in people with depression. It is estimated that 30% of individuals with Major depressive Disorder (MDD) fail to respond to conventional antidepressant medication. Treatment resistant depression (TRD) patients also are more likely to have other psychiatric and medical diagnoses, poorer quality of life, and increased suicidal ideation. There are few treatment strategies available to target TRD and there is not a lot of evidence about how TRD differs from depression that responds to treatment. In this study, the investigators will collect detailed information about participants psychiatric history and depression symptoms, as well as two brain scans using positron emission tomography (PET) and magnetic resonance imaging (MRI). PET imaging uses a radioactive agent (also called a tracer) to obtain pictures of the brain. The tracer used is called \[18F\]- SynVesT-1, which measures synaptic density. In addition, the MRI scan will be used to examine brain function when performing tasks involved in memory and learning about rewards. The ultimate goal of this study is to better understand synaptic density in the brain and how it relates to brain function during memory and reward learning tasks. This information will be important for advancing knowledge of the brain biology of TRD and potential new areas for treatment development.

Study Type

OBSERVATIONAL

Enrollment

Eligibility

Sex: ALLMin age: 25 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Key inclusion criteria for the MDD patients: * DSM-5 criteria for a Major Depressive Episode (MDE) within a MDD, confirmed through MINI diagnosis (Sheehan et al, 2015) * Age between 25 and 65 years * Hamilton Depression Rating Scale - 17 item (HRSD-17; Hamilton, 1960) \> 14 (moderate to severe symptoms) * Free of psychotropic medications (with the exception of SSRIs or SNRIs) for at least 5 half-lives before PET scanning per investigator discretion, after which an insignificant amount of drug is circulating through the body and accessing the brain. This determination will be based on self-report from the participant of when their last dose was. Use of benzodiazepines (except for diazepam) or sedative hypnotics (e.g. zopiclone) is allowable, but the last dose must be at least 72 hours prior to scanning. * Ability to undergo MRI scanning (absence of metal, pacemakers, etc.) * For non-resistant patients: Previous history of response to an antidepressant, in order to increase signal to noise between resistant and non-resistant patients Key inclusion criteria for the Healthy Controls: * Ages between 25 and 65 years * Ability to undergo MRI scanning (absence of metal, pacemakers, etc.) Exclusion Criteria: Key exclusion criteria for the MDD patients: * Pregnancy/lactation * Medical condition requiring immediate investigation or treatment * Recent (\< 6 months)/current history of drug abuse/dependence * Lifetime history of psychosis, other Axis I comorbidities are allowable * Use of any psychotropic use within 5 half-lives before the PET scanning, with the exception of SSRIs and SNRIs * For non-resistant patients: Failure of \> 2 antidepressant treatments of adequate dose and duration for current MDE. Key exclusion criteria for the Healthy Controls: * Pregnancy/lactation * Medical condition requiring immediate investigation or treatment * Lifetime history of any psychiatric disorder * Lifetime history of receiving an antidepressant

Outcomes

Primary Outcomes

Synaptic Density

Synaptic density represents a promising biomarker for TRD, as it provides a direct index of neural circuit integrity and synaptic architecture (Appelbaum et al, 2022; Serano et al, 2022). Interventions shown to be effective in treatment-resistant populations, including rapid-acting antidepressants and neuromodulatory approaches, have been proposed to engage in synaptic plasticity-related mechanisms (Duman et al, 2016). As such, synaptic density measured using SV2A PET may offer insight into circuit-level abnormalities relevant to depression severity and treatment resistance, therefore offering a mechanistically informed approach for characterizing the biological correlates of TRD and supports its use in PET-based investigations of this population

Time frame: 3 years

Characterizing Synaptic Density in Treatment Resistant Depression

Overview

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Outcomes

Primary Outcomes

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