Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct;2(7):566-574.
doi: 10.1016/j.bpsc.2017.04.006.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

Chadi G Abdallah  1   2 , Christopher L Averill  1   2 , Ramiro Salas  3   4 , Lynnette A Averill  1   2 , Philip R Baldwin  3   4 , John H Krystal  1   2 , Sanjay J Mathew  3   5 , Daniel H Mathalon  6
Affiliations

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

Chadi G Abdallah et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Oct.

Abstract

Background: Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine's mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr.

Methods: In study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction.

Results: In study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [-0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects.

Conclusions: This study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.

Keywords: Treatment resistant depression; functional MRI; global brain connectivity; glutamate; ketamine; rapid acting antidepressants.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interests CGA has served as a consultant and/or on advisory boards for Genentech and Janssen, and on editorial for Sage Publications, Inc. JHK is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Medical Sciences; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, U.S. Patent No. 5,447,948 (issued Sep 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued Jul 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on Mar 5, 2014); U.S. application or Patent Cooperation Treaty international application No. 14/306,382 (filed on Jun 17, 2014). SJM: In the past 12 months, Dr. Mathew has received consulting fees from Acadia, Alkermes, Allergan, Cerecor, Otsuka, and Valeant, and serves on an Advisory Board for VistaGen Therapeutics. He has received research support from Janssen Research & Development. DHM is a consultant for Boehringer Ingelheim, Takeda, Alkermes, and Upsher-Smith. All other authors report no competing interests.

Figures

Figure 1
Figure 1. Functional Dysconnectivity in TRD
(A) Voxel-wise comparisons of PFC GBCr showed significant reductions of GBCr in TRD, relative to HC, in three clusters (blue). (B) Ketamine increased GBCr 24h post-treatment in these clusters. The color bar depicts the z values of reduced (TRD < HC; blue) and increased (TRD > HC; yellow-red) GBCr. The black line delineates the PFC region. Abbreviations: TRD = Treatment-Resistant Depression; HC = Healthy Control; PFC = prefrontal cortex; GBCr = Global Brain Connectivity with global signal regression.
Figure 2
Figure 2. Effects of Lamotrigine and Ketamine on Prefrontal Functional Connectivity
(A) Voxel-wise paired t-tests with family-wise-error correction revealed significant reductions of GBCr 2h post lamotrigine (blue) and (B) increased GBCr during ketamine infusion (red). The color bar depicts the z values of reduced (blue) and increased (yellow-red) GBCr. The black line delineates the prefrontal cortex region. Abbreviations: GBCr = Global Brain Connectivity with global signal regression;
Figure 3
Figure 3. Interaction between lamotrigine and ketamine
Lamotrigine significantly inhibited the ketamine-induced GBCr surge. Abbreviations: GBCr = Global Brain Connectivity with global signal regression; Plc = Placebo; Ket = ketamine; Lamo = lamotrigine; * p < 0.05; * p < 0.01; * p < 0.0001
Figure 4
Figure 4. Prefrontal Limbic Connectivity
(A) Labels of the 4 major subnetworks within the prefrontal cortex (PFC). The ventral PFC (vPFC) area is colored with green. (B) TRD group had higher GBCr in the vPFC than the control group. (C) GBCr was numerically reduced in 7 of 10 TRD patients 24h post-ketamine treatment, but this reduction was not statistically significant. (D) In healthy subjects, ketamine significantly reduced vPFC GBCr during infusion. Abbreviations: GBCr = Global Brain Connectivity with global signal regression; TRD = Treatment-Resistant Depression;
Figure 5
Figure 5. Association Between Depression Treatment and Function Connectivity
(A) Correlation between ventral prefrontal cortex (vPFC) GBCr and the number of treatment failures as measured by the Antidepressant Treatment History Form (ATHF). (B) Correlation between improvement in depression severity and average baseline GBCr in the altered clusters. (C) The relationship between improvement in depression severity and baseline vPFC GBCr. Abbreviations: GBCr = Global Brain Connectivity with global signal regression; MADRS = Montgomery-Åsberg Depression Rating Scale; IDS = Inventory of Depressive Symptomatology.
See this image and copyright information in PMC

Comment in

References

    1. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17:111–126. - PMC - PubMed
    1. Coplan JD, Gopinath S, Abdallah CG, Berry BR. A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy. Frontiers in behavioral neuroscience. 2014;8:189. - PMC - PubMed
    1. Niciu MJ, Ionescu DF, Richards EM, Zarate CA., Jr Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna) 2014;121:907–924. - PMC - PubMed
    1. Murrough JW, Abdallah CG, Mathew S. Targeting glutamate signaling in depression: progress and prospects. Nature Reviews: Drug Discovery. 2017 In Press. - PubMed
    1. Zarate CA, Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864. - PubMed