Although these effects resolve approximately 2 h after acute ketamine use, long-term use can cause more pronounced and persistent neuropsychiatric symptoms, including schizophrenia-like symptoms, cognitive impairment and poor psychological well-being (Morgan et al., 2009, 2010; Liu et al., 2016). Despite the fact that a patent airway is usually maintained during exposure to ketamine, attention to airway protection remains essential, as partial obstruction and aspiration are still possible. Ketamine may increase salivary secretions (Corssen and Domino, 1966) and potentially increase the risk of laryngospasm, but this is rarely reported (Green et al., 2010). Other respiratory effects of ketamine include bronchodilation, likely through vagolytic and other neurally mediated mechanisms (Brown and Wagner, 1999). At high doses, ketamine may also directly affect airway smooth muscle, but this effect is unlikely to be of clinical importance (Brown and Wagner, 1999). Although initially developed as an anesthetic, over the past several decades ketamine has been revealed to have greater potential in the field of medicine.
- While intranasal S-ketamine clearly has some beneficial effects in the treatment of depression, the magnitude of these effects, among other things, remains a matter of debate [115–117].
- The drug is a Schedule III non-narcotic that the Food and Drug Administration (FDA) has approved for use only as a general anesthetic.
- In a subsequent study, Skolnick et al. [131] demonstrated that chronic treatments with traditional antidepressants alter radioligand binding to NMDARs in the cerebral cortex.
- Bonhomme et al. (2016) presented functional MRI data from human volunteers whereby ketamine disrupted cortical connectivity between frontal and posterior cortices, while auditory and visual network integrity was maintained.
- Once in the body, ketamine undergoes liver metabolism to several metabolites (Clements and Nimmo, 1981).
Mechanism of Action
Reduction in activity was observed in large regions throughout the brain, including areas related to the DMN. Several studies by the same group support the notion of ketamine normalizing patterns of brain activity in MDD patients [202, 228, 230]. There has been surging interest in the use of ketamine as a potential therapeutic john carter author at sober home agent for affective disorders, particularly depression. Even a single-dose of ketamine may cause rapid antidepressant effects in otherwise treatment-resistant cases of bipolar (DiazGranados et al., 2010b; Ibrahim et al., 2011; Kantrowitz et al., 2015) and major depression (Zarate et al., 2006; Murrough et al., 2013).
Ketamine as an antidepressant drug
Future studies aimed at addressing these and other basic questions will hopefully advance our understanding of the pharmacological and neurobiological mechanisms of ketamine in the treatment of psychiatric disorders. These changes are thought to be mediated by the blockade of extrasynaptic NMDARs containing GluN2B subunits [149]. In contrast, several recent studies suggest that ketamine’s effects are mediated through its HNK metabolites independently of NMDAR inhibition (Fig. 3b) [134]. Altogether, these hypotheses are not mutually exclusive and may together explain the molecular changes observed after ketamine administration. The majority of studies concerning the antidepressant effects of ketamine have focused on investigating intravenous administration, in which doses are determined by the subject’s weight. In contrast, trials for intranasal ketamine typically use predetermined bolus doses.
Cellular-level findings in animal models
Ketamine is on the World Health Organisation’s list of essential medicines, because it’s extremely useful as an anaesthetic in locations where ventilation equipment isn’t available. Although its slight psychedelic effects don’t make it an ideal anaesthetic in general, because it doesn’t impact on breathing rates as much as other anaesthetics do, it’s extremely useful in the field, or in locations where it’s harder to access such equipment. Because it doesn’t lower blood pressure it’s also useful as a painkiller in emergency trauma situations as well. It’s also the case that tolerance to the drug can build up, meaning higher doses are required for a user to get the same effect, which can increase the risk of bladder damage.
Near-death experience
(The exception would be when a patient is imminently suicidal, in which case the treatment would often be started while the patient is hospitalized.) What counts as “trying” an oral antidepressant? As a general rule, at least 4 weeks of treatment cyclobenzaprine: muscle relaxer uses side effects and dosage are required before it can be known if an antidepressant is helpful. A 2022 review found that long-term, high dose use of recreational ketamine may be linked to brain function-related side effects, mood disorders, and psychotic symptoms.
Intensive research efforts aimed at understanding the precise mechanisms underlying ketamine’s effects have resulted in important advances in our understanding of depression and stimulated new concepts of molecular and cellular neuropharmacology. However, as with anything new, the glimmer of ketamine may have distracted both basic and clinical researchers from addressing fundamental issues. Certain questions, such as whether increasing doses in patients that respond poorly to lower doses is beneficial and whether anesthetic doses lack antidepressant effects, remain unanswered. There are also no comprehensive comparisons of the effectiveness of different administration routes or the rate and time administration. Moreover, the circadian time, dose, and method of administration in animal studies often differ significantly from those in clinical practice and lack proper translational validation.
Gonadal hormones, such as estrogen and progesterone, may also potentiate the rapidity and potency of ketamine’s antidepressant effects, as demonstrated in preclinical models (Carrier and Kabbaj, 2013; Franceschelli et al., 2015; Hashimoto, 2016). Lastly, ketamine interaction with GABA receptors has been implicated in various clinical pathologies, including obsessive-compulsive disorder (Rodriguez et al., 2015), depression (Perrine et al., 2014) and learning disabilities following chronic exposure (Tan et al., 2011). To our knowledge, this work provides an initial demonstration that acute ketamine-induced changes in anterior insula reactivity to negative emotional stimuli depend upon specific aspects of dissociative experiences and other ASCs. These findings shed light on the neurobiological mechanisms that underlie ketamine’s ability to both acutely relieve negative affective states and induce them in nonclinical participants. Furthermore, if these results are extended to patients with depression, they should advance scientific understanding about how aspects of intra-infusion ASCs might predict depression response—results that might help inform more personalized treatment interventions.
Indeed, investigation into ketamine’s antidepressant effects have led to several reports that ketamine may affect various brain regions through epigenetic mechanisms, such as histone deacetylase modulation (Reus et al., 2013; Choi et al., 2015) and increased BDNF mRNA expression (Duman and Voleti, 2012). Although there has been a substantial increase in preclinical research regarding ketamine’s neuroprotective potential over the past two decades, uncertainty persists at each mechanistic step. At the cell membrane, ketamine clearly functions as an NMDA antagonist, but whether this is required for all forms of ketamine’s ultimate neuroprotective actions is less clear.
In addition, Wray et al. (2019) identified a novel mechanism by which ketamine might exert its neuroprotective effect. This effect was present after subunit GluN1 knockdown, demonstrating the possibility of yet another NMDAR-independent mechanism of ketamine (Wray et al., 2019). While GluN3/GluN2 subunits display a substantial reduction in glutamate or glycine-activated currents, the actions of ketamine on review of answer house sober living GluN1 lacking NMDARs remains poorly defined (Smothers and Woodward, 2007). Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes.
Since ketamine is used broadly in veterinary research and medicine, non-rodent animal subjects are also viable models for study and could be used to help bridge the gap between basic science and clinical research. In addition, some standardization among cell-culture based models would allow us to obtain a more unified perspective on ketamine’s actions. Rather than focusing solely on particular nodes in the proposed mechanistic pathways, “omics”-based approaches may offer a more unbiased appreciation of the spectrum of ketamine’s cellular effects. Finally, it will be important to continue to develop and investigate analogs of ketamine that might serve as alternatives with decreased neurotoxic potential and reduced psychotomimetic effects. Studies examining the involvement of AMPAR activation in ketamine’s mechanism of action have largely focused on the antidepressant effects of ketamine; a role for AMPAR signaling in broader forms of neuroprotection has not been addressed with as much vigor. Several other membrane receptors have also been demonstrated to bind ketamine, including sigma-1 receptors, nicotinic acetylcholine receptors, voltage gated calcium channels, and HCN channels (Lavender et al., 2020).
Due to ketamine’s high lipid solubility and relatively limited protein binding, it is rapidly taken up by the brain and redistributed, with a distribution half-life of only 10–15 min (Wieber et al., 1975; Domino et al., 1984). Ketamine has a large volume of distribution of nearly 3 L/kg (Clements and Nimmo, 1981). Once in the body, ketamine undergoes liver metabolism to several metabolites (Clements and Nimmo, 1981). Of note, metabolism through cytochrome systems forms the active metabolite norketamine, which retains anesthetic activity but at one-third the potency of ketamine (Cohen and Trevor, 1974; Domino et al., 1984). Inactive ketamine conjugates and metabolites are renally excreted (Wieber et al., 1975), and elimination half-life is 2–3 h (Domino et al., 1984).
The drug is also popular for recreational use because of its dissociative effects. According to the Drug Enforcement Administration (DEA), recreational forms of ketamine are commonly known as Special K, KitKat, Vitamin K, and other slang terms. Unlike most other agents, ketamine offers the important advantage of being able to provide both profound analgesia and adequate sedation without significantly compromising airway reflexes or respiratory function (Corssen and Domino, 1966). It is thus often used in acute clinical settings, though there is a growing interest in its role as a chronic therapeutic agent as well.
Moreover, positive allosteric AMPAR modulators produce antidepressant-like behavioral effects in rodents (Knapp et al., 2002; Li et al., 2001) and upregulate BDNF synthesis [159, 160]. Our mediation findings might help to account for potentially inconsistent findings across studies, methodologies, and healthy versus clinical participants. When we considered the group effects in our trial, without considering variability in different aspects of dissociation, ketamine induced an increase in the average threat-faces-evoked reactivity of the right anterior insula and right amygdala compared to placebo.
Participants completed the 5D-ASC scale after scanning was complete and were instructed to rate retrospectively as if they were 20 min into the infusion. In addition to the above quantitative assessments, we used keywords from the CADSS and 5D-ASC to prompt participants to describe their experience, and we recorded narratives for the last five participants (P09–P13). The second intracellular pathway implicated in inducing BDNF upregulation in response to subanesthetic ketamine treatment involves the eukaryotic elongation factor 2 kinase (eEF2K) as responsible for BDNF upregulation (Monteggia et al., 2013). Autry et al. (2011) focused on eEF2K rather than mTOR and found that ketamine’s fast-acting and sustained antidepressant responses required AMPAR activation and BDNF translation through the deactivation of eEF2K. In line with these findings, one study demonstrated that memantine’s inability to inhibit the phosphorylation of eEFK2 precluded it from upregulating BDNF expression and imparting an antidepressant effect (Gideons et al., 2014). The antidepressant effects of (2R-6R)-HNK (10 mg/kg intraperitoneally or 50 μM bath application) also include eEF2 inactivation (Zanos et al., 2016; Suzuki et al., 2017) and mice with deletions of eEF2K do not display ketamine-induced antidepressant effects (Nosyreva et al., 2013).