Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition
Bernhard Luscher, Mengyang Fenga, Sarah J. Jefferson
Advances in Pharmacology, 2020
doi : 10.1016/bs.apha.2020.03.002
1. Introduction 3
2. Molecular targets of subanesthetic ketamine and its metabolites 6
3. Insights from ketamine indicate a key role for reduced GABAergic inhibition in the pathophysiology of major depression 7
3.1 Antidepressant efficacy of ketamine is controlled by imbalances between neural excitation and inhibition 7
3.2 Chronic imbalances of neural excitation and inhibition lead to homeostatic downregulation of glutamatergic synapses that compromises normal neuronal communication 9
3.3 Chronic imbalances between neural excitation and inhibition lead to defects in GABAergic inhibition that delimit spontaneous recovery from transient excesses in excitation 10
4. GABAergic interneurons serve as the initial cellular targets of subanesthetic
4.1 Direct hypothesis of ketamine-induced synaptic plasticity 12
4.2 Indirect or disinhibitory hypothesis of ketamine-induced synaptic plasticity 14
4.3 NMDA receptors on somatostatin- and parvalbumin-positive GABAergic interneurons serve as the initial targets of ketamine 15
5. The mechanism of ketamine-induced plasticity includes a sustained increase in GABAergic synaptic inhibition at dendrites 17
5.1 Ketamine-induced antidepressant effects are associated with sustained pre- and postsynaptic enhancement of GABAergic synaptic inhibition 17
5.2 Genetic enhancement of GABAergic inhibition at pyramidal cell dendrites mimics the lasting antidepressant behavioral and biochemical consequences of ketamine in the drug-off situation 20
6. Conclusion 22
Conflict of interest 24
There has been much recent progress in understanding of the mechanism of ketamine’s rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses.
This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto
increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.
Major Depressive Disorder (MDD) is the leading cause of ill health and disability with more than 300 million afflicted people worldwide and a cost to the global economy of a trillion US dollars every year (WHO, 2017). Conventional antidepressants that target monoaminergic neurotransmitter systems are widely available but often ineffective and they suffer from a pronounced delay in therapeutic efficacy of weeks to months.
Accordingly, patients who are resistant to treatment often end up in a lengthy and futile pursuit of treatment while at high risk of self-harm and suicidal behavior ( Jick, Kaye, & Jick, 2004). However, much hope has emerged in recent years from ketamine, which following administration of a single subanesthetic dose has rapid antidepressant effects that are significant already within a couple hours and last for up to 1 week even in otherwise treatment-resistant patients (Fava et al., 2019; Lapidus et al., 2014; Murrough et al., 2013; Singh et al., 2016; Zarate et al., 2006).
The mechanism underlying ketamine’s antidepressant effects is strikingly different from that of conventional antidepressants. This is evidenced by the rapid onset of action and by the therapeutic benefits being observed almost exclusively after the drug has been eliminated from the brain (referred to
here as the “drug-off” situation) (Berman et al., 2000; Zarate et al., 2006). Other telling features of ketamine’s mechanism observed in patients and animal models include the inverted U-shaped dose-response curve (Fava et al., 2019; Kim & Monteggia, 2020; Moghaddam, Adams, Verma, & Daly, 1997; Su et al., 2017) and the rapid yet transient increase in extracellular glutamate (Lorrain, Baccei, Bristow, Anderson, & Varney, 2003; Moghaddam et al., 1997; Rotroff et al., 2016) that then triggers a wave of synaptogenesis that reverses a functional deficit in neural connectivity associated with depression (Abdallah Averill, Collins et al., 2017; Abdallah, Averill, Salas et al., 2017; Chowdhury et al., 2017; Evans et al., 2018; Kraguljac et al., 2017; Li et al., 2010; Moda-Sava et al., 2019).
Preclinical studies further indicate that ketamine-induced synaptogenesis and the antidepressant behavioral responses are critically dependent on the function of AMPA receptors and a neural activity-induced increase in the synthesis and release of neurotrophic factors such as BDNF (Autry et al., 2011; Deyama, Bang, Kato, Li, & Duman, 2019; Li et al., 2010).
Ketamine represents a racemic mixture of equal parts of R-()-ketamine (arketamine) and S-(+)-ketamine (esketamine). Racemic R/S-ketamine was first approved by the United States Food and Drug Administration (FDA) in 1970 as a rapidly acting dissociative anesthetic, analgesic, sedative and amnesic and remains on the World Health Organization’s List of Essential Medicines (Green et al., 1998; Reich & Silvay, 1989). Ketamine acts as a noncompetitive antagonist and open channel blocker of NMDA-type glutamate-gated cation channels (NMDA receptors) (Hirota & Lambert, 1996). That is, ketamine requires membrane depolarization-mediated removal of a Mg2+ ion from the channel for access to the channel pore. Notably, ketamine has lower affinity (>10 μM) at multiple other receptors and neuro-transmitter transporters that may contribute to its therapeutic and side effects at anesthetic concentrations (Tyler, Yourish, Ionescu, & Haggarty, 2017). However, there is no evidence that
these targets are relevant at subanesthetic doses. Nevertheless, even at subanesthetic doses, ketamine exhibits dissociative and psychotomimetic properties and abuse potential reminiscent of other NMDA receptor antagonists (Krystal et al., 1994; Sassano-Higgins, Baron, Juarez, Esmaili, & Gold, 2016; Short, Fong, Galvez, Shelker, & Loo, 2018; Thomson, West, & Lodge, 1985). These features confirm NMDA receptors as key targets but also limit adoption of ketamine as an antidepressant outside of the clinic.
Therefore, a detailed understanding of ketamine’s mechanism of action is fundamentally important for the design of superior agents that act similarly but with fewer side effects and with potential for wider adoption. In addition, studies of ketamine’s mechanism of action have provided pivotal new
key insights into the pathophysiology of depressive disorders.
Initial exploratory clinical studies of ketamine’s antidepressant properties were conducted off-label with an intravenous 40min infusion of racemic ketamine (0.5mg/kg) (Berman et al., 2000; Zarate et al., 2006). Then, in March 2019, the (S)-enantiomer esketamine (Spravato) was approved by the FDA as a nasal spray specifically for treatment-resistant depression (Canuso et al., 2018; Popova et al., 2019; Singh et al., 2016; U.S. Food and Drug Administration, 2019). As might be expected of anNMDAreceptor
antagonist, ketamine has profound effects on glutamatergic neurotransmission, which has bolstered the view that depressive disorders reflect dysregulation of glutamatergic transmission (Musazzi, Treccani, & Popoli, 2012; Paul & Skolnick, 2003; Sanacora, Treccani, & Popoli, 2012; Thompson et al., 2015). However, it is important to note that ketamine’s action as an NMDA receptor antagonist by itself says little about the nature and cause of dysregulated glutamate function. Changes in glutamatergic transmission are implicated in a wide range of neuropsychiatric and neurological conditions and they do not occur in isolation. Rather they involve upstream and/or downstream changes in other neuro-transmitter systems that may be more specifically associated with depressive disorders. In particular, changes in glutamatergic transmission and NMDA receptor activity are in a tight bidirectionally inverse relationship with changes in GABAergic inhibitory transmission. While diverse NMDA receptor antagonists have shown antidepressant-like properties in preclinical tests (Trullas & Skolnick, 1990), ketamine to this day remains the only such agent that shows robust and sustained antidepressant activity in patients (Gould, Zarate, & Thompson, 2019; Newport et al., 2015). Collectively, this suggests that
NMDA receptors are not the only target relevant for ketamine’s antidepressant action. Indeed, as detailed below, ketamine is rapidly metabolized into multiple compounds, including some that appear to contribute to its antidepressant mechanism through other targets. Moreover, there is rapidly emerging evidence that ketamine has prominent effects not only on glutamatergic but also GABAergic synaptic transmission and other neurotransmitter systems. Here we review the mechanisms underlying
ketamine-induced synaptic plasticity and antidepressant behavioral consequences with special emphasis of the role of GABAergic synaptic transmission and inferences that can be drawn from these observations to explain the pathophysiology of MDD.