Ketamine acts as a rapid antidepressant in about 70% of patients. It has stereoselective binding profiles and metabolic pathways that vary between its (S) and (R) enantiomers. Research on ketamine's mechanism of action and pharmacokinetics faces challenges due to its use as a racemic mixture in animal studies and the small number of brain targets studied relative to the complexity of the human central nervous system.

1. Ketamine acts as a rapid antidepressant in about 70% of patients
Dr. Gerry Higgins
Research Professor, Computational Medicine & Bioinformatics
University of Michigan Medical School

2. KETAMINE

3. Structures of enantiomers of (A) ketamine and (B) norketamine
The asterisk indicates the chiral center of the molecule

4. Metabolic pathway of the racemic mixture (R)(S)-ketamine;
(R)(S)-norketamine is the most active metabolite
Most other ketamine analogs in RCTs as an antidepressant
are not metabolized, or are metabolized by other CYPs or DAO.

5. Cook-Sather SD et al (2016). CYP2B6*6 or Not CYP2B6*6—That Remains a
Question for Precision Medicine and Ketamine! Anesthesiology: The Journal of
the American Society of Anesthesiologists, 125(6), 1085-1087.

6. Challenges associated with research into the pharmacokinetics
of the racemic mixture (R)(S)-ketamine
1. Most ketamine-like drugs in development as antidepressants are not
metabolized, are metabolized by CYP2D6 or DAO, but are not
metabolized by CYP2B6 [1];
2. CYP2B6 is the most inducible CYP gene in human liver (2000-fold),
and is highly induced in brain by drugs such as nicotine, as well as
ketamine [2, 3];
3. CYP genes are more highly expressed among regions of human
brain than they are in human liver [4].
[1] Murrough JW et al (2017). Targeting glutamate signaling in depression: progress and
prospects. Nature Reviews Drug Discovery, 16(7), 472.
[2] Garcia, K. L., Lê, A. D., & Tyndale, R. F. (2017). Brain CYP2B induction can decrease
nicotine levels in the brain. Addiction Biology. 22(5), 1257-1266.
[3] Aroke EN et al (2017). Pharmacogenetics of ketamine-induced emergence
phenomena: A pilot study. Nursing Res. 66(2), 105-114.
[4] Li G et al (2018). HT-eQTL: integrative expression quantitative trait loci analysis in a
large number of human tissues. BMC Bioinformatics. 19(1), 95.

7. The CYP2B6 and CYP2D6 Genes are Expressed at Higher Levels in
Human Brain than in Human Liver
A: Li G et al (2018). HT-eQTL: integrative expression quantitative trait loci analysis in a large number of human
tissues. BMC Bioinformatics. 19(1), 95;
B: Sunkin SM et al (2012). Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous
system. Nucleic Acids Research. 41(D1), D996-D1008.
B
A

8. Overview of possible mechanism of action of ketamine as an antidepressant
Pharmacodynamics of the racemic mixture (R)(S)-ketamine

9. Target Species Binding affinity / Inhibition constant Stereoselectivity
NMDAR Human 𝐾𝑖 = 0.7 ± 0.3 mM (SK), 2.3 ± 0.3 mM (RK) SK has 3-fold affinity of RK
DRD2 Human 𝐾𝑖 = 12 ± 0.8 mM Not measured
DRD4 Human 𝐾𝑖 = 26 ± 1.1 mM Not measured
OPRM1 Guinea pig 𝐾𝑖 = 11 mM (SK), 28 mM (RK) SK has 2.5-fold affinity of RK
OPRK1 Guinea pig 𝐾𝑖 = 24 mM (SK), 100 mM (RK) SK has 4-fold affinity of RK
OPRD1 Guinea pig 𝐾𝑖 = 130 mM (SK), 130 mM (RK) No significant difference
CHMR4 Guinea pig 𝐾𝑖 = 131 mM (SK), 19 mM (RK) RK has 4-fold affinity of SK
HTR3A Human 𝐼𝐶50 = 910 ± 30 mM Not measured
HTR2C Human 𝐾𝑖 = 35 mM (SK), 19 mM (RK) RK has 1.8-fold affinity of SK
HTR1A Human 𝐼𝐶50 = 16 ± 1.4 mM Not measured
HTR1B Human 𝐾𝑖 = 6 ± 0.2 mM Not measured
AMPAR Human 𝐾𝑖 = 7 ± 0.5 mM (SK), 24 ± 2.0 mM (RK) SK has 3.5-fold affinity of RK
GABRA1 Human 𝐾𝑖 = 134 ± 29 mM Not measured
GABBR1 Human 𝐾𝑖 = 144 ± 32 mM Not measured
SLC6A2 Human 𝐾𝑖 = 67 ± 26 mM Not measured
SLC6A3 Human 𝐾𝑖 = 46.9 mM (SK), 390 mM (RK) SK has 8-fold affinity of RK
SLC6A4 Rat 𝐾𝑖 = 162 ± 28 mM Not measured
Binding affinity and stereoselectivity of (R)(S)-ketamine in the CNS

10. Challenges associated with research into the pharmacodynamics
of the racemic mixture (R)(S)-ketamine
1. The majority of the published literature in neuroscience since 1975
that used animal studies for examination of CNS pathways have
used (R)(S)-ketamine as the anesthetic, thus potentially confounding
experimental results essential to understanding ketamine’s pathways
in brain;
2. AMPAR, BDNF, CREB1, DRD2, HTR1A, HTR1B, MAPK1, MTOR,
NMDAR, OPRK1, OPRM1, SLC6A2, SLC6A3 and SLC6A4 account
for over 15,000 (>50%) of the research articles published in
molecular neuroscience since 1995, but represent less than 0.005%
of the functional molecules in the human CNS [1, 2, 3].
[1] Dolgin E (2017). The most popular genes in the human genome. Nature. 551, 427-
431.
[2] César-Razquin, A et al. (2015). A call for systematic research on solute
carriers. Cell, 162(3), 478-487.
[3] Higgins GA, Allyn-Feuer A, Georgoff P, Nikolian VC, Alam HB, and Athey BD (2017)
Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug
pathways. Methods 123: 102-118

11. Measure (S) / (R) ratio
Anesthetic potency 3
Analgesic potency 3 - 4
Antidepressant potency 2 - 3
Incidence of psychotomimetic effects at equianesthetic
doses
0.14
Incidence of psychotomimetic effects at equianalgesic
doses
1
Incidence of psychotomimetic effects at equivalent
antidepressant dose
0.5 - 1
Affinity for the PCP binding site in human brain 6 - 7
Volume of distribution at steady state 1.1
In vivo plasma clearance rate 1.1
In vitro hepatic clearance rate in human liver microsomes 1.2
Potency and stereoselectivity of (R)(S)-ketamine

12. (R)(S)-ketamine
Clinical Indications and Dosing
(R)(S)-ketamine
Incidence of Adverse Drug Events

13. Examples of PET neuroimaging results showing human brain regions
that are activated following i.v. infusion of ketamine
(A) Patients with treatment-resistant depression who responded to 0.5 mg/kg ketamine
infusion had significantly higher glucose metabolism in the supplementary motor area
(SMA) and dorsal anterior cingulate cortex (dACC) than did those who do not
respond to the lower dose of 0.2 mg/kg ketamine infusion.
(B) PET imaging of a marker of glucose metabolism identifies intravenous ketamine
activation in multiple brain regions in healthy controls versus placebo. Regions
include dorsal cingulate cortex, subgeniculate cingulum, habenula and other regions.
A B