Author: John Carter

Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression PMC

In addition, early data suggests that ketamine might enhance negative self-schemas, which is one of the primary therapy goals of CBT [16]. In a pilot that studied white matter connectivity, chronic ketamine users showed higher connectivity between caudate nuclei and the dorsal anterior cingulate cortex (dACC). Furthermore, in ketamine users, the putamen showed higher connectivity to the OFC, which correlated with duration of ketamine use.

Regarding the safety of repeated ketamine infusions, it remains unclear whether ketamine treatment for TRD further increases risk for the development of addiction. While it is important to further examine the addictive properties of ketamine, repeated low-dose infusions have had groundbreaking therapeutic value in reducing suicidal ideation in TRD individuals. It remains unclear, though, if repeated infusions of ketamine will increase propensity for ketamine abuse or relapse to other addictive drugs following antidepressant treatment. To answer this, studies examining the effects of slow, low-dose ketamine infusions on subsequent ketamine self-administration are necessary. Studies examining the antidepressant effects of repeated (R)-ketamine infusions across different doses are also necessary to potentially reduce risk for abuse and cognitive deficits.

First, there is continuing pursuit of compounds seeking to replicate ketamine’s antidepressant effects without dissociative effects. In particular, several new avenues implicated in the mechanistic processes of ketamine’s antidepressant effects beyond NMDAR inhibition are now being explored that are likely to shed light on possible links between antidepressant response and dissociation. Another proposed mechanism suggests that ketamine’s antidepressant effects are NMDAR-independent and occur through ketamine’s metabolites; of these, (2R,6R)-hydroxynorketamine (HNK) is of particular interest34,67. Intriguingly, a recent study from our laboratory found that ketamine and NK plasma levels—but not (2R,6R)-HNK levels—were uniquely related to increased dissociative symptoms (as assessed via CADSS score) in participants with TRD68. Furthermore, the (2R,6R)-HNK metabolite may be particularly dependent on AMPARs and, thus, would not have dissociative side effects or abuse potential.

Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression

Specifically, transient positive symptoms were seen after THC administration, as measured by the Positive and Negative Symptoms Scale (PANSS). Psychotic TRD represents the most severe presentation of MDD, characterized by a high mortality rate and unfavorable prognosis [1]. Recent studies have begun to uncover how intracellular signaling mechanisms that produce the acute antidepressant action of ketamine transition to a sustained effect that may last over a week [104]. Second, the sustained effect relies on transcriptional regulation, which is elicited by the initial synaptic plasticity.

Neuroimaging studies have indicated that the cingulate cortex is the primary site of ketamine’s effect. The bulk of blood-based, neuroimaging, and neurophysiological studies reviewed demonstrate that ketamine induces normalization of major depressive disorder aetiology through synaptic plasticity and functional connectivity. Currently, no biomarker/biosignature has been well validated for clinical use, although some seem intriguing [34]. A possible mechanism for the white matter changes identified in the reviewed recreational ketamine studies could be AMPA-receptor mediated excitotoxicity. In rats, ketamine was found to acutely elevate presynaptic glutamate in the prefrontal cortex at AMPA/kainite receptors (Moghaddam et al., 1997), and prolonged ketamine exposure may provoke cell death by regional glutamate-induced excitotoxicity. Excitation of AMPA receptors specifically induces axonal damage (Fowler et al., 2003), which could provide a potential mechanism for the prominent white matter changes observed after sustained ketamine exposure in three of the reviewed studies.

Furthermore, according to the results of this study, the authors found that high doses of mephedrone cause a fast release of dopamine and serotonin from the nucleus accumbens, but conversely, the elimination rate of dopamine was as fast as the one of amphetamine, leading to a more potent and robust stimulation of the addiction circuits (76). As mephedrone use became more popular, many authors began to study the pharmacodynamics of this new psychoactive drug, finding, in particular, an increase of dopamine release and inhibition of the reuptake of monoamines (15–19). Furthermore, being completely water-soluble, it can be injected intramuscularly or intravenously, or even taken by rectal administration using a needle-free syringe (74). When taken orally, mephedrone starts to give effects to consumers within 15–45 min after ingestion; when snorted the effects can be felt in minutes with a higher peak, usually reached after 30 min.

Dopamine D1 Receptors

Mice with the BDNF Val66Met polymorphism, which impairs trafficking of BDNF mRNA to dendrites, also show attenuated responses to ketamine [101], although ketamine appears to retain efficacy in humans who are homozygous for the Met allele of BDNF [49]. The form of synaptic scaling elicited after ketamine administration discussed above has also been shown to be strictly dependent on BDNF-TrkB signaling [60, 95, 98]. As an update of the abovementioned work, the most important finding is the increased number and variety of new psychoactive drugs.

1. Lin et al. used resting state fMRI to compare a group of chronic ketamine users, many of which also used other drugs like cannabis or cocaine, to healthy controls (Liu et al., 2016).
2. The neurobiological underpinning of cannabis-induced psychotic symptoms, is however still not completely clear.
3. In depressed patients who had responded to antidepressant treatment, depletion of either serotonin or norepinephrine prevented or transiently reversed the antidepressant effects of serotonin transporter antagonists or norepinephrine transporter antagonists, respectively [14,15,16].
4. Furthermore, patients with a previous history of substance-induced psychosis could present severe psychotic symptoms mainly with delusions after smoking Spice, and other SCs (61, 67, 70).
5. In the late Seventies, observing that an acute administration of amphetamines produced an accurate phenocopy of schizophrenia, several authors theorized that amphetamine-induced psychosis could be used as a model of schizophrenia (113) and that its continuous use could itself cause its development (114).

The initial pilot study used the previously ketamine infusion strategy to conduct the first randomized, placebo-controlled test of ketamine response in depression [26]. This study built on inconclusive findings with lower potency NMDAR antagonists including amantadine and memantine [27]. The investigative team also was aware of earlier studies in animals that described antidepressant effects of NMDAR partial agonists and antagonists [28, 29]. However, none of these studies predicted the distinctively rapid and robust antidepressant effects of a single ketamine dose in depressed patients observed in the initial pilot study, nor the efficacy in treatment-resistant symptoms of depression, bipolar disorder [30] or suicide ideation [31].

Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics?

It is possible that reward-circuitry activation is partly responsible for mediating the antidepressant actions of ketamine. Indeed, ventral striatum activation during positron emission tomography (PET) imaging was increased following two ketamine infusions (0.5 mg/kg, i.v.) in depressed subjects and correlated with the score of antidepressant response (Nugent et al., 2014). Along the same line, using magnetoencephalography (MEG), subjects’ ratings of a “blissful state” during a low-dose ketamine infusion (0.25 mg/kg bolus, 0.375 mg/kg/1 h, i.v.) correlated positively with increased frontoparietal activation (Muthukumaraswamy et al., 2015). Given that human cocaine addicts also show frontoparietal activation when exposed to drug-related stimuli (Costumero et al., 2017), it is possible the same neurocircuitry mediating the antidepressant effects of ketamine could also contribute to its abuse potential.

Structural Differences: Gray Matter

Third, since subjects were mostly recreational users, they might have used ketamine shortly before data were obtained. Therefore, the different functional connectivity patterns could in part be caused or influenced by the direct, short term effects of ketamine. The figure depicts an alternative basic synaptic circuit where an excitatory pyramidal neuron receives inputs from other excitatory neurons, where inhibitory inputs regulate the extent of glutamate release from primary excitatory neurons. 1, it highlights the role of NMDA receptors on inhibitory neurons and their impact on regulation of glutamate release. According to this “disinhibition” model, ketamine predominantly acts on inhibitory interneurons, curtailing their tonic NMDAR dependent activity and in turn augmenting excitability of glutamatergic neurons as well as ensuing glutamate release.

Furthermore, juvenile male mice exposed to ceftriaxone, an EAAT2-antagonist, did not exhibit ketamine-induced reduction in hippocampal EAAT2 expression during adulthood. These results suggest that repeated, low-dose ketamine administration restricted to the period of adolescence leads to cognitive impairments that are mediated by increased extracellular glutamate as a result of reduced glutamate clearance, and can have long-lasting behavioral and molecular effects in adulthood. As noted above, recent research with SPs such as psilocybin, LSD, DMT, and Ayahuasca suggest that these compounds may also lead to rapid antidepressant effects. Notably, the psychoactive state with SPs appears to be integral to the antidepressant effects of these agents; treatment thus often incorporates the psychedelic experience into assisted therapy18.

Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion

Have not yet been examined in the context of cognition in TRD patients, healthy volunteers still experience dissociative effects when administered 0.3 mg/kg, i.v., but not 0.1 mg/kg, i.v. The findings may help to inform the development of new treatments for psychosis that target NMDA receptors or brain noise,” he added. Despite the considerable progress in this area, one key remaining question is the link between ketamine’s side effects and its antidepressant effects. In initial testing in the 1960s, individuals receiving ketamine described feeling “spaced out” or “dreaming” when administered subanesthetic doses23.

Subsequent monitoring revealed no exacerbation of psychotic symptoms in short and long-term observation, while stable remission was observed in all cases with imminent antisuicidal effect. Results suggest ketamine may benefit individuals with treatment-resistant depression with psychotic features. The convergence of the broadening perspective of the biology of depression with the development of an approach to probe glutamate synaptic function resulted in the discovery of the rapid antidepressant effects of ketamine.

Juvenile male rats injected with an effective antidepressant dose of ketamine (20 mg/kg, i.p.) were more sensitive to its acute locomotor-activating effects as compared to adults (Parise et al., 2013; Rocha et al., 2017). However, sensitization to the locomotor activating effects of ketamine occurred in both adolescent and adult male rats (Rocha et al., 2017). At lower doses of ketamine (3–10 mg/kg, i.p.), which is an ineffective antidepressant dose in male juvenile rats, adult, but not juvenile male rats, developed ketamine-induced sensitization to its locomotor activating effects (Wiley et al., 2008). Interestingly, at these lower doses (3–10 mg/kg, i.p.), female juvenile and adult rats developed sensitization to ketamine locomotor activating effects (Wiley et al., 2011).