Connectivity changes after ketamine in treatment resistant depression and receptor expression

466 

Abstract Submission 

Jen Evans¹, Carlos Zarate²

¹NIH, Bethesda, MD, ²National Institute of Mental Health/NIH, Bethesda, MD

Jen Evans  
NIH
Bethesda, MD

Carlos Zarate, MD  
National Institute of Mental Health/NIH
Bethesda, MD

The rapid acting antidepressant ketamine is described as being a glutamatergic modulator (Zarate, 2017) but its exact mechanism of action remains an active area of research. Recent developments in making neurotransmitter atlases available enables the investigation of the overlap of functional changes and receptor density. Robust changes in the BOLD signal have been measured after a ketamine infusion (McMillan, 2020) but most studies have been performed in healthy volunteers with drug doses that differ from that administered in clinical treatment. Here we investigate functional connectivity changes administration in unmedicated patients with treatment resistant major depression in conjunction with receptor density maps.

Fourteen patients (mean age 35 years, [19-61]) with treatment resistant major depression underwent a double-blind placebo cross-over trial where they received either a 40 minute infusion of either 0.5 mg/kg racemic ketamine or saline placebo while they were being scanned in a 3T Siemens Skyra scanner with 1 week between each infusion. Briefly, a 15 minute eyes closed resting state scan was acquired prior to (baseline) and from approximately 20-35 minutes after the start of the infusion (post). Multi-echo fMRI data (3mm isotropic, TR: 2.08 s, TEs: 13,27,47 ms, FA: 75 degrees) was preprocessed with afni_proc with slice-timing correction, motion alignment, registration to MNI space, and spatial smoothing to 4mm and anaticor. Correlation matrices were generated for each scan using 3dNetcorr (Taylor, 2013) using the Schaefer 100 parcellation (Schafer, 2018) and split into positive and negative change matrices. Neuromaps was used to generate receptor density maps following Hansen et al., 2022. Receptor densities were correlated against correlation changes using python's scipy.stats module.

Figure 1a illustrates the group average correlation change (baseline – post) matrices for the ketamine (ket) and placebo (pbo) sessions. The post-ketamine scan has widespread connectivity changes, which show regional specificity. Figure 1b shows the spatial locations of the positive and negative edges of the correlation changes. For reference, figure 2a shows the spatial distribution of glutamate receptors displayed using the same functional parcellation. The connectivity changes during the ketamine infusion are correlated against the density of glutamate receptors in figure 2b, demonstrating a weak but significant correlation between the negative edges (R2 :0.08 p: 0.004) but not for the positive (R2 :0.02 p: 0.13). Several other receptors also demonstrate significant relations notably serotonin (5HT*), mu opioid (MOR), cannabinoid (CB1) and muscarinic (M1). Interestingly, there was not a strong relation with functional changes and NMDA receptors which have also been implicated in ketamine's mechanism of action. Comparable motion values were measured between paired ketamine and placebo scans suggesting that this result is not an effect of increased motion during drug administration.

The very early functional connectivity changes expressed by this depressed patient sample during a ketamine infusion reflect glutamatergic receptors involvement commensurate with ketamine's expected mechanism of action. Relating functional changes to the neurotransmitter architecture may be a step towards bridging preclinical development of drugs and their application in the clinic. Further, using individualized correlations with behavioral changes may help investigate differences in behavioral response.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

fMRI Connectivity and Network Modeling ²

Pharmacology and Neurotransmission

FUNCTIONAL MRI

Glutamate

Psychiatric Disorders

Other - ketamine; depression