Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites
Chun Yang, Jianjun Yang, Ailin Luo and Kenji Hashimoto
Translational Psychiatry, 2019, 9, 280
doi : 10.1038/s41398-019-0624-1
Although the robust antidepressant effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman’s group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal regulated kinase possibly underlie the antidepressant effects of (R)-ketamine.
Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF–TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.
Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs), are widely prescribed for the treatment of depression in patients with major depressive disorder (MDD). However, there is a significant time lag of weeks to months for the anti-depressant effects of these drugs to be achieved in patients with MDD1. In addition, approximately one-third of patients with MDD do not experience satisfactory therapeutic benefits following treatment with SSRIs or SNRIs1. Importantly, the delayed onset of these antidepressants is extremely harmful to patients with depression who experience suicidal ideation (2,3).
Therefore, the development of rapid-acting and robust antidepressants is imperative to relieve the symptoms of severe depression and suicidal ideation in patients with MDD or bipolar disorder (BD) (4–12).
In 2000, Berman et al.13 demonstrated that a subanesthetic dose (0.5 mg/kg) of ketamine, an N-methyl-Daspartate receptor (NMDAR) antagonist, produced rapidacting and sustained antidepressant effects in patients with MDD. This is a first double-blind, placebo-controlled study of ketamine in depressed patients (13). Subsequently, Zarate et al.14 replicated the rapid-acting and sustained antidepressant effects of ketamine for patients with treatment-resistant MDD. In addition, ketamine possesses robust antidepressant effects in patients with bipolar depression (15–18). Ketamine has been shown to alleviate suicidal ideation in patients with treatment-resistant MDD (19–21). Several meta-analyses revealed that ketamine has robust antidepressant and anti-suicidal ideation effects in depressed patients with treatment-resistant MDD or BD (2,3,22,23).
The antidepressant effects of ketamine have attracted increasing academic attention due to its effects being rapid-acting and long-lasting effects in treatment-resistant depression (8,12,24). Although ketamine has a robust antidepressant effect, its side effects may limit its widespread use for the treatment of depression (12,25–31). Ketamine has detrimental side effects, which include psychotomimetic effects, dissociative effects, and abuse liability; which may be associated with the blockade of NMDAR (25,26,32). It is known that dissociative symptoms following ketamine infusion are not associated with its clinical benefits (24), suggesting that NMDAR inhibition may not serve a key
role in the antidepressant effects of ketamine. Fava et al. (33) also reported that there were no statistically significant correlations between Clinician Administered Dissociative States Scale (CADSS) scores 40 min after the ketamine infusion and Hamilton Depression Rating Scale-6 (HAMD-6) scores at day 1 and day 3 in treatmentresistant patients with depression, in contrast to the hypothesis by Luckenbaugh et al. (34). In addition, brainimaging findings suggest that reduced subgenual anterior
cingulate cortex is implicated in the antidepressant effects of ketamine in humans (35,36). However, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unclear. In this review article, recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites are summarized.
Enantiomers of ketamine
Ketamine (Ki=0.53 μM for NMDAR) (Fig. 1) is a racemic mixture consisting of equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). The binding affinity of (S)-ketamine (Ki=0.30 μM) for NMDAR is ~4- fold greater than that of (R)-ketamine (Ki=1.4 μM) (Fig. 1) (37). Furthermore, the anesthetic potency of (S)-ketamine is ~3–4-fold greater and the undesirable psychotomimetic side effects are greater than those of (R)-ketamine (38). We reported that (R)-ketamine has more potent and longer-lasting antidepressant-like effects than (S)-ketamine in neonatal dexamethasone-treated, chronic social defeat stress (CSDS), and learned helplessness (LH) models of depression (39,40). Subsequent studies have also shown that (R)-ketamine has more potent antidepressant-like effects than (S)-ketamine in rodents (41,42). A recent study showed that the order of antidepressant-like effects in a CSDS model following the intranasal administration is (R)- ketamine > (R,S)-ketamine > (S)-ketamine (43), and that the order of side effects in rodents is (S)-ketamine > (R,S)-
ketamine > (R)-ketamine (43). The side effects of (R)-ketamine in rodents were lower than those of (S)-ketamine (40,43–45). A positron emission tomography study showed a marked reduction in dopamine D2/3 receptor binding in the conscious monkey striatum following a single intravenous infusion of (S)-ketamine but not that of (R)-ketamine, suggesting that the (S)-ketamine-induced dopamine release may be associated with acute psychotomimetic and dissociative side effects in humans (46).
In 1995, Mathisen et al. (47) reported that the incidence of psychotomimetic side effects of (S)-ketamine in patients with orofacial pain was higher than that of (R)-ketamine, despite the dose of (S)-ketamine (0.45 mg/kg) being lower than that of (R)-ketamine (1.8 mg/kg). In addition, Vollenweider et al. (48) reported that (R)-ketamine did not produce psychotic symptoms in healthy subjects and that the majority experienced a state of relaxation, whereas the same dose of (S)-ketamine caused psychotic reactions including depersonalization and hallucinations. These findings suggest that (S)-ketamine contributes to the acute side effects of ketamine, whereas (R)-ketamine may not be associated with these side effects49. Importantly, non-ketamine NMDAR antagonists (i.e., memantine, traxoprodil, lanicemine, rapastinel, and AV-101) did not exhibit robust ketamine-like antidepressant effects in patients with MDD (12,22,23). These clinical findings suggest that NMDAR may not be the primary target for the antidepressant effects of ketamine.
Taken together, (R)-ketamine is considered to be a safer antidepressant than (R,S)-ketamine and (S)-ketamine in humans (12,50–52). On March 5, 2019, the US Food Drug Administration (FDA) approved (S)-ketamine nasal spray for treatment-resistant depression. However, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy due to the risk of serious side adverse outcomes. A clinical trial of (R)- ketamine in humans is currently underway by Perception Neuroscience, Inc. (12).