Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography

Marie Spies, Gregory M James, Neydher Berroterán-Infante, Harald Ibeschitz, Georg S Kranz, Jakob Unterholzner, Mathis Godbersen, Gregor Gryglewski, Marius Hienert, Johannes Jungwirth, Verena Pichler, Birgit Reiter, Leo Silberbauer, Dietmar Winkler, Markus Mitterhauser, Thomas Stimpfl, Marcus Hacker, Siegfried Kasper, Rupert Lanzenberger, Marie Spies, Gregory M James, Neydher Berroterán-Infante, Harald Ibeschitz, Georg S Kranz, Jakob Unterholzner, Mathis Godbersen, Gregor Gryglewski, Marius Hienert, Johannes Jungwirth, Verena Pichler, Birgit Reiter, Leo Silberbauer, Dietmar Winkler, Markus Mitterhauser, Thomas Stimpfl, Marcus Hacker, Siegfried Kasper, Rupert Lanzenberger

Abstract

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans.

Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest.

Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown.

Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.

Trial registration: ClinicalTrials.gov NCT02717052.

Keywords: antidepressant; ketamine; positron emission tomography; serotonin transporter.

© The Author 2017. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
(a) No measurable occupancy of the serotonin transporter (SERT) after 0.50 mg/kg bodyweight ketamine. [11C]DASB nondisplaceable binding potential (BPND) decreased numerically from positron emission tomography (PET) 1 (left, before ketamine application) to PET 2 (right, after application of the standard antidepressant dose of 0.50 mg/kg bodyweight ketamine) in the caudate, putamen, and thalamus. Mean occupancy values ± SD of the SERT were 5.86±21.88, 2.70±13.76, and 1.11±23.27, respectively. Results were interpreted as a lack of measurable binding, because occupancy values are within [11C]DASB test-retest variability (Kranz et al., 2015) (see supplement). Color bar represents [11C]DASB BPND. Slices at z=10 (caudate), z=6 (putamen), and z=12 (thalamus). For [11C]DASB BPND and occupancy values see Table 1. (b) Correlation between ketamine plasma levels and SERT occupancy. Ketamine plasma levels assessed after ketamine administration during PET correlated with SERT occupancy within the caudate and putamen (caudate 20 min: P=.042; 30 min: P=.018; putamen 30 min: P=.031, all uncorr., min indicate time after start of PET measurement). Though the correlations are influenced by outliers, these findings might suggest that ketamine may bind the SERT when levels are higher, for example, when ketamine is administered at higher doses or depending on differences in metabolism (Zarate et al., 2012; Zhao et al., 2012). Correlation analyses with ketamine plasma levels drawn 30 minutes after PET start are depicted. Correlations may be significant at this time point, as ketamine kinetics are known to switch from the distribution to elimination phase around this time (Hijazi et al., 2003). *Indicates statistical significance of correlations (P<.05, uncorrected). For occupancy values and ketamine plasma levels, see Tables 1 and 2.
Figure 2.
Figure 2.
Ketamine plasma levels. Ketamine plasma levels were in accordance with those previously described in the literature (Zarate et al., 2012). PET measurement began 5 minutes after completion of the ketamine infusion (0.50 mg/kg bodyweight over 40 min) and ketamine plasma levels were drawn 5, 10, 20, 30, 40, 60, and 80 minutes after the start of PET. The 5-minute ketamine value from 1 subject was removed from analyses due to probable blood draw error. For ketamine plasma levels see Table 2.

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