Given that this is the only study to date to examine the effects of repeated, low-dose ketamine on cognition in both sexes and ketamine administration occurred neonatally, it is difficult to interpret whether the observed effects would be the same if ketamine administration occurred during adulthood. Furthermore, all of the above-mentioned studies occurred in stress-naïve rodents, and given that stress itself can induce cognitive deficits, it remains unclear what the effect of repeated treatment with low-dose ketamine would be on cognition in a chronically stressed state in both sexes. In line with clinical studies, a single intraperitoneal (i.p.) injection of low-dose ketamine (5–10 mg/kg) elicits rapid antidepressant-like effects in adult male rodents, demonstrated by areduction in forced swim test (FST) immobility time, an antidepressant effect that is sustained for 3–7 days (Li et al., 2010; Autry et al., 2011). Furthermore, our lab was the first to show that adult female rodents are more sensitive to the acute antidepressant effects of ketamine, responding to a dose (2.5 mg/kg, i.p.) that was sub-threshold in male rats (Carrier and Kabbaj, 2013).
One study investigated how long-term ketamine use affected neurotransmitter systems (Narendran et al., 2005). Dopamine D1 binding potential was studied using positron emission tomography (PET) imaging after intravenously injecting the selective D1 receptor radio ligand 11CNNC 112 in 14 ketamine users with a mean use of 0.75 gram/week for 4.1 years and 14 drug-free controls. D1 receptor availability was significantly upregulated in the dorsolateral prefrontal cortex of ketamine users compared to controls, which could result from increased receptor density or affinity. D1 binding potential correlated with the total amount of ketamine consumption (Narendran et al., 2005). In a pilot that studied white matter connectivity, chronic ketamine users showed higher connectivity between caudate nuclei and the dorsal anterior cingulate cortex (dACC).
General Health
In 16 ketamine users averaging 2.4 grams/day for 7.3 years, a lower level of axial diffusivity was found compared to 16 polydrug controls, especially in the frontal part of the right hemisphere (Edward Roberts et al., 2014). Axial diffusivity was significantly lower in eight white matter clusters in the right hemisphere in the ketamine group compared to the control group, the three largest being located in the frontal cortex (Edward Roberts et al., 2014). Also, probabilistic tractography was performed to investigate cortico-subcortical white matter connectivity profiles, which revealed that white matter connectivity between the caudate nucleus and the lateral prefrontal cortex was positively correlated with severity of long-term dissociative symptoms (Edward Roberts et al., 2014).
However, in the reduced perceptual environment of the MRI scanner (Figure 2, right panels), perceptual expectations are already being violated, which triggers prediction error responses that are exacerbated by ketamine. A more robust top-down response is mounted (as a result of the sensory isolation) and hallucinations result. We have proposed that this enhanced top-down response is mediated by the slow neuromodulators dopamine and acetylcholine 27, which have been shown to mediate attentional gain on incoming sensory information 33 and encode salience of environmental stimuli 34. Here we present data from a set of solution-focused therapy interventions healthy participants who received moderately dosed, placebo controlled ketamine infusions in the reduced stimulation environment of the magnetic resonance imaging scanner.
Clinical Measures
- Of these 7, many reported that cochlear implant placement had made the musical hallucinations less prominent but 2 reported that they became louder with implantation 38.
- It is possible that reward-circuitry activation is partly responsible for mediating the antidepressant actions of ketamine.
- All cases described correspond with previous literature reports on safety and tolerability, with neither relevant cardiovascular and hemodynamic changes nor psychomimetic exacerbations in the acute treatment phase as well as in the follow-up.
Also, ketamine subjects showed lower activation in the cerebellum and the middle temporal cortex in response to natural rewarding (sexual) cues (Liao et al., 2018). Psychotic treatment-resistant depression is a complex and challenging manifestation of mood disorders in the clinical setting. Psychotic depression is a subtype of major depressive disorder characterized by mood-consistent hallucinations and/or delusions.
However, it should be noted that the neuroimaging studies, to date, have only examined the acute effects of ketamine; thus, neuroimaging studies combined with chronic ketamine treatment are necessary to elucidate the mechanism mediating the long-term antidepressant effects of ketamine as well as its abuse potential. It should be noted that the studies mentioned above assessed the effects of repeated ketamine only in stress-naïve rodents. Recently, studies have reported the use of ketamine, albeit at higher doses (30 mg/kg, i.p.), as prophylactic to prevent negative outcomes of stressful situations. This was demonstrated in male mice where prophylactic ketamine prior to stress reduced freezing in a fear conditioning paradigm (McGowan et al., 2017). It will be thus interesting to determine whether such effects seen in male adult mice would be replicated in adult female and juvenile male and female mice. Gray matter volumes in rOFC, rMPFC and rNAC were negatively correlated with ketamine dependence severity and gray matter volumes of the rOFC, rmPF, lCN, lGP, lH, and rNAC negatively correlated with cognitive performance (Liu et al., 2016; Tang et al., 2016).
Potential clinical implications
Part of the structural and functional neuroanatomical differences could therefore be attributed to these concomitant conditions. Additionally, quantitative approaches to ketamine’s effects on sensory processing have produced results that match qualitative reports of sensory amplification. Plourde and colleagues 32 determined that, unlike most general anesthetics, ketamine produces an increase in auditory event-related gamma-band oscillations in patients administered anesthetic doses. Similar increases in gamma-band oscillations have also been demonstrated in somatosensory evoked potentials in subjects administered sub-anesthetic ketamine13. In the context of predicted normal ambient input, top-down priors can be mobilized, resulting in delusion-like interpretations of aberrant salience, but not hallucinations 27 (Figure 2, left panels).
However, no studies to date have examined the effects of repeated, low-dose ketamine in chronically stressed adolescents, which may have different effects on cognition and neural circuitry. Thus, while studies are beginning to shed light on the effects of low-dose ketamine during adolescence, it is difficult to interpret in the context of depression. Repeated administration of ketamine at low doses (5 mg/kg, i.p.) to male mice induced hippocampal CA3 cell death, demonstrated by caspace-3 labeling, suggesting that repeated exposure to low doses of ketamine induces apoptotic effects in stress-naïve male rodents (Majewski-Tiedeken et al., 2008) (Table 2). It is therefore important to examine whether similar effect would be observed in mice that were chronically stressed. These data suggest that baseline cognition may predict sensitivity to the cognitive-altering effects of ketamine. Future studies should consider screening for kaiser drug treatment baseline cognitive performance prior to treating TRD patients with repeated ketamine infusions.
This can include periods of remission, as well as acute episodes of psychosis, in which their schizophrenia symptoms worsen. Schizophrenia is a how to recover from being roofied persistent and complex condition with many factors contributing to its causes. Research does indicate that the type of drug a person takes before an episode of substance-induced psychosis can be a predictor of whether they will later develop schizophrenia.
