Pattern Separation in Major Depressive Disorder

Jeffrey Miller

Status and phase

Not yet enrolling

Phase 1

Conditions

Major Depressive Disorder (MDD)

Treatments

Drug: Extended-Release Memantine

Drug: SSRI (escitalopram or sertraline)

Drug: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT07139834

00081503

Details and patient eligibility

About

This study seeks to examine the effects of treatment with a selective serotonin reuptake inhibitor (SSRI), escitalopram, a first-line treatment for depression, in combination with placebo or with extended-release memantine, on neuropsychological function, regional brain activity assessed by functional magnetic resonance imaging, and depressive symptoms, in participants with Major Depressive Disorder. Escitalopram is administered in an open-label fashion in this study; extended release memantine is administered in a double-blind, randomized, placebo-controlled manner.

Full description

Pattern separation is the process of separating overlapping sensory information, contexts, or experiences into distinct neural representations. In humans, deficits in pattern separation are believed to underlie overgeneralization seen in depression and post-traumatic stress disorder (PTSD). Cross-sectional data support the effects of SSRI medications on pattern separation. Specifically, a recent paper demonstrated patients with depression who responded to SSRI medication had improved pattern separation performance (mnemonic discrimination) of emotionally neutral stimuli than SSRI non-responders, and that the findings were reversed with respect to emotionally negative stimuli (Phillips et al., 2023). These data are consistent with the negative cognitive bias in depression (Beevers et al., 2019), and provide indirect evidence of SSRI effects on pattern separation in humans. However, there is a dearth of longitudinal, within-subject analyses of SSRI effects on pattern separation performance, and associated neural activity quantified by BOLD signal from fMRI.

In the current study, we seek to examine the individual effect of SSRI treatment (in combination with placebo) as compared to the combined effect of treatment with SSRI and memantine, an NMDA-antagonist, on pattern separation, both in terms of behavioral performance and activity in the dentate gyrus as assessed by fMRI, and on depression severity. We propose to study individuals with major depressive disorder in a current major depressive episode who are currently unmedicated, who will undergo baseline medical and psychiatric assessment and fMRI scanning, followed by standardized treatment with escitalopram combined with either placebo or memantine in the context of a double-blind, placebo-controlled, randomized clinical trial.

Enrollment

30 estimated patients

Sex

All

Ages

18 to 50 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age 18-50
Current diagnosis of MDD without psychotic features assessed within three weeks of study enrollment
17-item Hamilton Depression Rating Scale score ≥17 assessed within 3 weeks of study enrollment
Using an effective form of contraception at study enrollment and agrees to continue throughout study participation for individuals of child-bearing potential
Capacity to provide informed consent
Proficient in English
Willing to provide emergency contact

Exclusion criteria

Currently taking an antidepressant medication at study enrollment
Pregnant or breastfeeding at time of enrollment
Evidence of current unstable medical illness, including liver or renal impairment, or unstable cardiovascular or respiratory illness
QTc interval greater than 500 ms
Current genitourinary conditions that raise urine pH such as a) renal tubular acidosis or b) severe infection of the urinary tract.
Clinically significant neurological conditions, including a) history of stroke, b) previous head injury with evidence of cognitive impairment, c) history of malignancy or d) history of seizure disorder. (headache, migraines, pain disorders, and other conditions not exclusionary)
Lifetime diagnosis of a) bipolar disorder, b) psychotic disorder, or c) dementia
Current active suicidal ideation
Current substance use disorder other than tobacco use disorder
Current or recent (past 6 months) treatment with antipsychotics; current or recent (past 1 month) treatment with benzodiazepines; current use of prescribed stimulant medication; current use of other NMDA antagonists (amantadine, ketamine, dextromethorphan)
Current use of disulfiram with oral concentrate, MAOIs (including linezolid or IV methylene blue), or pimozide
History of hypersensitivity or allergic reaction to a) memantine hydrochloride or any of its components/excipients, b) citalopram, escitalopram, or any other component of the product, or c) sertraline or any other component of the product
Concurrent or recent (past 6 months) participation in another clinical trial for mental illness involving an investigational product or device
Lack of response to or intolerable side-effects from trials of two or more selective serotonin reuptake inhibitors of adequate dose and duration at study enrollment
Electroconvulsive therapy (ECT) in the past 6 months
Any condition or material in the body that is a contraindication for MRI procedures
Weight that exceeds 300 lbs or inability to fit into MRI scanner
MST LDI score greater than 0.5