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Journal of Clinical and
Basic Psychosomatics The antidepressant effect of ketamine

Ketamine, a glutamatergic modulator with rapid 2.1. Brain morphology
antidepressant effects, has proven effective in treating Brain morphological changes include alterations in gray
both refractory depression and suicidal tendencies. The matter volume, white matter volume, cortical thickness,
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neurobiological mechanisms underlying the effects of density, and white matter fiber integrity. Gray matter
antidepressants have become a research hotspot, but the volume, white matter volume, cortical thickness, and
exact processes remain uncertain. Noteworthy, despite its density can be measured using high-resolution three-
rapid antidepressant effects, the application of ketamine to dimensional structural T1 MRI, while white matter fiber
treat depression is still in its infancy, with many unresolved integrity can be measured using DTI.
problems. For instance, the addiction risk associated with
the use of ketamine as an antidepressant has not been The most common morphological change observed
determined, the total duration of treatment remains is in the volume of the hippocampus. Zhou et al.
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unconfirmed, and how to address dissociative symptoms reported that the right hippocampal volume significantly
has not been established. These questions might benefit increased after six serial ketamine infusions for 12 days,
from the discovery of corresponding biomarkers. proposing increased hippocampal volume as a prominent
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Brain imaging studies have provided important evidence neurobiological biomarker. Abdallah et al. found that
from macroscopic perspectives, such as brain structure and ketamine treatment increased the left hippocampal
function, while biochemical studies have made significant volume but reduced the volume of the left nucleus
discoveries from microscopic perspectives, including accumbens in patients who achieved remission. They also
proteomics and genomics. To scientifically clarify the noted that pretreatment volumes of the left hippocampal
were associated with clinical response following ketamine
neurobiological mechanisms of ketamine’s rapid-acting infusions. In addition to the hippocampus, a decrease
antidepressant effects, we searched for relevant literature in the volume of the right dorsolateral prefrontal cortex
from five electronic databases (2000 – 2023), PubMed, the
Cochrane Library, EMBASE, the Web of Science, and clinical (dlPFC) was found to be associated with the antidepressant
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trials, using the following terms: “depression,” “ketamine,” effect of ketamine. Furthermore, a study investigating
“rapid-acting,” and “biomarker.” A total of 87 articles were gray matter density changes after ketamine treatment
included in this review. We reviewed studies related to the in bipolar depression patients revealed decreased gray
neurobiological mechanisms underlying the rapid-acting matter density in the bilateral insula, right caudate, and
antidepressant effects of ketamine from both macro- and bilateral dlPFC, and increased gray matter density in the
microperspectives (Figure 1), identifying hot topics and bilateral post-central gyrus, subgenual anterior cingulate
potential strategies for future investigations. Ultimately, this cortex (sgACC), thalamus, and cerebellum. These changes
review provides evidence for the development of accurate appeared 24 h post-ketamine treatment, peaked at 1 week,
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rd
and individualized treatments for depression. and diminished by the 3 week.
DTI studies have also revealed important structural
2. Neuroimaging markers alterations in white matter fiber tracts associated with the
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Multiple neuroimaging modalities have been used to efficacy of ketamine. Sydnor et al. showed that fractional
explore the mechanisms of the rapid antidepressant anisotropy (FA) in the forceps minor and bilateral uncinate
effects of ketamine. Neuroimaging can identify functional fasciculus increased after ketamine treatment. In addition,
connections and networks associated with the effects of baseline FA values of the left cingulate tract and the upper
ketamine therapy by revealing how ketamine alters brain longitudinal tract were significantly correlated with the
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structure, function, connectivity, and metabolism. For effect of ketamine. In the study by Vasavada et al., patients
example, high-resolution three-dimensional structural who responded to ketamine had significantly greater FA
T1 magnetic resonance imaging (MRI) can measure in the cingulum and forceps minor at baseline compared
differences in volume, thickness, and density in cortical to non-responders, with a complementary decrease in the
and subcortical structures; diffusion tensor imaging (DTI) radial diffusivity of these tracts.
can assess the integrity of white matter fiber tracts; positron 2.2. Brain metabolism and hemodynamics
emission tomography (PET) can detect brain glucose
metabolism levels through radiotracer labeling; arterial PET, a technology with moderate temporal and spatial
spin labeling (ASL) can detect cerebral blood flow; and resolution, can effectively detect brain metabolic levels.
functional MRI (fMRI) can measure brain activation level. Carlson et al. found that metabolism decreased in the right
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In this section, three aspects of the rapid antidepressant insula, habenula, and ventrolateral and dorsolateral PFCs
effects of ketamine are reviewed: morphology, metabolism, after ketamine treatment. In addition, acute improvement
hemodynamics, and brain function. in depression was significantly correlated with metabolic

Volume 2 Issue 3 (2024) 2 doi: 10.36922/jcbp.2596