Table 1.
Summary of sex differences in response to acute ketamine treatment.
| Reference | Species | Stress | Ketamine dose (i.p.) |
Readout | Time post injection |
Ketamine effects in Males vs Females |
|---|---|---|---|---|---|---|
| Behavioral correlates | ||||||
| Carrier and Kabbaj, 2013 | Rats (SD) | No stress | 2.5–10 mg/kg |
FST + NSFT | 30 min | Reduced immobility and latency to feed at 2.5, 5, and 10 mg/kg in females, but only at 5 and 10 mg/kg in males. |
| Carrier and Kabbaj, 2013 | Rats (SD) | No stress | 2.5–10 mg/kg |
Acute SPT | 48 hrs | Increased sucrose preference at 5 and 10 mg/kg in males only (ceiling effect in females). |
| Franceschelli et al., 2015 | Mice (C57BL/6J) |
No stress | 3, 5, 10 mg/kg |
FST | 30 min | Reduced immobility at 3, 5, and 10 mg/kg in females, but only at 5 and 10 mg/kg in males. |
| Franceschelli et al., 2015 | Mice (C57BL/6J) |
No stress | 3, 5, 10 mg/kg |
FST | 24 hrs | Reduced immobility at 5 and 10 mg/kg in females, but only at 10 mg/kg in males. |
| Saland et al., 2016 | Rats (SD) | No stress | 2.5 mg/kg | Continuous SPT monitoring |
Up to 7 days |
Hedonic effect sustained up to 7 days in females only, in an ovarian hormones-dependent manner. |
| Zanos et al., 2016 | Mice (CD-1) |
No stress | 1, 3, 10 mg/kg |
FST | 24 hrs | Reduced immobility at 3 and 10 mg/kg in females, but only at 10 mg/kg in males. |
| Franceschelli et al., 2015 | Mice (C57BL/6J) |
Stress (CMS) | 10 mg/kg | Acute SPT | 6 days | No effect in either sex. |
| Franceschelli et al., 2015 | Mice (C57BL/6J) |
Stress (CMS) | 10 mg/kg | FST | 1 or 7 days | Reduced immobility at day 1 and 7 in males, but only at day 1 in females. |
| Franceschelli et al., 2015 | Mice (C57BL/6J) |
Stress (CMS) | 10 mg/kg | Splash test | 5 days | Reversed CMS-induced reduction in grooming behavior in males, but not females. |
| Sarkar and Kabbaj, 2016 | Rats (SD) | No stress + Stress (IS) |
2.5, 5 mg/kg | FST | 3–5 days | Reduced immobility at 2.5, and 5 mg/kg in females, but only at 5 mg/kg in males. |
| Molecular correlates | ||||||
| Carrier and Kabbaj, 2013 | Rats (SD) | No stress | 2.5, 5 mg/kg | Protein expression in mPFC |
30 min | Increased mTOR phosphorylation in both males and females at 5, but not 2.5 mg/kg. Reduced eEF2 in the male HPC at 5 mg/kg; no effect in females. |
| Saland et al., 2016 | Rats (SD) | No stress | 2.5 mg/kg | Protein expression |
24 hrs | Up-regulation of BDNF in treatment-responsive females, but not males. |
| Sarkar and Kabbaj, 2016 | Rats (SD) | Stress (IS) | 2.5, 5 mg/kg | Dendritic spine density in mPFC |
3 hrs | Reversed stress-induced spine loss at 5 mg/kg in males but not in females. |
| Sarkar and Kabbaj, 2016 | Rats (SD) | Stress (IS) | 2.5, 5 mg/kg | Synaptic protein expression in mPFC |
3 days | Reversed stress-induced down-regulation of synapsin I, PSD95, and GluR1 at 5 mg/kg in males but not in females. |
| Pharmacokinetics | ||||||
| Zanos et al., 2016 | Mice (CD-1) | No stress | 10 mg/kg | Ketamine metabolites |
0–60 min | Higher HNK but not K or NK levels in the brain of females following ketamine administration. |
| Saland et al., unpublished |
Rats (SD) | No stress | 2.5 mg/kg | Ketamine metabolites |
0–180 min | Greater K and NK levels in the plasma and brain of females at early timepoints, but HPC and mPFC specificities in magnitude. |
| Zarate et al., 2012 | Humans | MDD/BP patients |
0.5 mg/kg (i.v.) |
Ketamine metabolites |
40–1,440 min | Higher DHNK and HNK4a/c plasma levels in female MDD and bipolar patients than males. |
| Sigtermans et al., 2009 | Humans | Healthy | 40 ng/ml/15 min (i.v.); 320 ng/ml max |
Ketamine, Norketamine |
2–300 min | Higher S(+)-K and -NK plasma levels in healthy females compared to males, associated with greater female clearance. |
Only experimental data displaying a sex difference are reported. BP: Bipolar Disorder, CMS: Chronic Mild Stress, DHNK: Dehydronorketamine, FST: Forced Swim Test, HNK: Hydroxynorketamine, HPC: Hippocampus, IS: Isolation Stress, K: Ketamine, mPFC: medial Prefrontal Cortex, MDD: Major Depressive Disorder, NSFT: Novelty-suppressed Feeding Test, NK: Norketamine, SD: Sprague-Dawley, SPT: Sucrose Preference Test.