Rapid Anti-Depressant Relief by Ketamine: Exploring A ......Ketamine at low doses has been shown in clinical trials to induce a rapid, short-lived anti-suicide and anti-depressant

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Current Psychopharmacology, 2019, 8, 1-16 1

REVIEW ARTICLE

2211-5560/19 $58.00+.00 © 2019 Bentham Science Publishers

Rapid Anti-Depressant Relief by Ketamine: Exploring A Complex Mechanism of Action

Kenneth Bluma,b,d,*, Todd C. Pappasc, Bryan Cliftonc, David Barona,b, Margaret A. Madiganb, Lisa Lottb, Mark Moranb,c, Cannon Cliftonc, Scott Worrichc, Ervey Clarkec, Brent Boyettd, Abdalla Bowirrate and Mark S. Goldb,f

aWestern University Health Sciences, Graduate School of Biomedical Sciences, Pomona, CA; bDivision of Nutrigenomics, Geneus Health, LLC., San Antonio, TX; cKalypso Wellness Centers, San Antonio, TX; dDivision of Neuroscience & Addiction Therapy Research, Pathways Health, Birming-ham, AL; eDivision of Anatomy, Biochemistry and Genetics Faculty of Medicine and Health Scienc-es, An-Najah National University, Nablus, Palestine; fDepartment of Psychiatry, Washington Uni-versity School of Medicine, St. Louis, MO

Abstract: Background: Suicide rates and narcotic overdose have doubled since 2000. At least 30 percent of people with major depression are Treatment-Resistant (TR) and require novel therapeutics. Ketamine at low doses has been shown in clinical trials to induce a rapid, short-lived anti-suicide and anti-depressant effect.

Objectives: To review the potential mechanism of action of ketamines’ alleviation of depressive symptoms from both animal and available human literature.

Methods: This is a synthesis of information from papers listed in PUBMED Central. Although not exhaustive, this review highlights the most compelling work in the field related to this remarkable clinical rapid anti-depressant effect.

Results: While there have been several theories and with some scientific evidence to date, the conclusion here is that currently, an exact and acceptable mechanism of action (MOA) for ketamines’ rapid anti-depressant effect is not apparent. The MOA of this compound with psychoactive abuse potential at a higher dosage and acute anti-depressive effect in the most resistant patients is unknown.

Discussion: Possible MOAs reviewed, include dopamine receptor modulation through epigenetic neuroadaptation via specific D1/D2 antagonism, D1 activation using opto-genetic stimulation, and the role of D2/D3 availability in the ketamine therapeutic ac-tion.

Conclusion: Unraveling MOA could guide the development of other unique Psycho-plastogens capable of rapidly promoting structural and functional neural plasticity in cases of TR Major Depressive Episodes (MDE) and unipolar Major Depression Disor-der (MDD).

A R T I C L E H I S T O R Y

Received: July 09, 2019 Revised: July 22, 2019 Accepted: August 12, 2019 DOI: 10.2174/2211556008666190827150018

Keyword: Dopamine, ketamine, Mechanism of Action (MOA), rapid antidepressant effect, Treatment Resistant Depression (TRD).

*Address correspondence to this author at the Western University Health Sciences, Graduate School of Biomedical Sciences, Pomona, CA; Tel: 1619980-2167; E-mail: [email protected]

2 Current Psychopharmacology, 2019, Vol. 8, No. 2 Blum et al.

1. INTRODUCTION

Suicide rates and narcotic overdose have dou-bled since 2000. At least 30 percent of people with major depression are Treatment-Resistant (TR) and require novel therapeutics. Ketamine at low doses has been shown in clinical trials to induce a rapid, short-lived anti-suicide and anti-depressant effect.

1.1. Prevalence Data for Major Depressive Dis-order (MDD)

The prevalence data for Major-Depressive-Episodes (MDE) are from the 2016 National Sur-vey on Drug Use and Health (NSDUH). The study definition is: “Two weeks or longer during which there is either depressed mood or loss of interest or pleasure, and four or more symptoms that reflect changes in functioning, such as problems with energy, sleep, eating, self-image, concentration, or recurrent thoughts of death or suicide. Unlike the definition in the DSM-IV, there were no exclu-sions for MDE caused by medical illness, be-reavement, or substance use disorders” [1].

In 2016, of more than 10 million U.S. adults aged 18 or older with a major depressive episode, 64% had at least one major depressive episode with severe impairment. This number represented 4.3% of all U.S. adults. Moreover, the combined number of deaths among Americans from suicide and unintentional overdose doubled to 110,749 in 2017 and has exceeded the number of deaths of diabetes. Indeed, this increase includes opioid overdose deaths, as well as those related to Major Depressive Disorder (MDD). It is known that chronic effects of prescribed potent analgesics im-pact dopamine release at the Nucleus Accumbens (NAc) by dysregulation of the glutaminergic drive at the Ventral Tegmental Area (VTA) [2, 3]. Increasing mortality rates highlight the need to investigate medications that may effect the glutaminergic system like Psychoplastogens that have rapid onset and possibly better response rates to treat resistant patients with MDE.

1.2. A Paradigm Shift in Approaches to Treat-ing Brain Disorders

Olson, D. E. [4] in 2018 suggested that the abil-ity to change and adapt in response to stimuli (neu-

ral plasticity) is an essential aspect of healthy brain function that might become the basis of treatment for a wide variety of brain disorders. Many neuro-psychiatric diseases, including mood, anxiety, and substance use disorders, arise from an inability to weaken the pathologic and strengthen beneficial neurological circuits, ultimately leading to mala-daptive behavioral responses [3]. Therefore, com-pounds capable of facilitating the structural and functional reorganization of neural circuits to pro-duce positive behavioral effects have broad thera-peutic potential. Several known drugs and experi-mental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow acting. However, evidence suggests that in humans, ketamine increases glutamate re-lease in the prefrontal cortex, a mechanism previ-ously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects [4].

The goal here is to present a minireview, to bring together pertinent animal and human articles from the literature that identify possible mecha-nisms of action of ketamine, and to explore ques-tions about how ketamine alleviates depressive symptoms, why the effects are both rapid and short-lived, as well as, elucidate the addictive and dissociative side-effects.

2. WHAT IS KETAMINE?

Ketamine is a synthetic anesthetic, used in low doses in Vietnam where it became established as an effective anesthetic /analgesic. Ketamine is part of a recently discovered class of fast-acting thera-peutic Psychoplastogenic compounds including psychedelics that have short-lived antidepressant therapeutic effects. They are capable of rapidly promoting structural and functional neural plastici-ty and must be considered in cases of treatment-resistant (TR) Major Depressive Episodes (MDE). The use of Psychoplastogenic medications in psy-chiatry represents a paradigm shift in approaches to treating brain disorders that emphasizes selec-tive modulation of neural circuits and focuses less on rectifying "chemical imbalances" [4]. The ef-fects of ketamine include neuroplasticity, the re-construction of neural networks through neu-rotrophic effects. Zhang et al. [5] provided some evidence showing in rodents that subanesthetic

Rapid Anti-Depressant Relief by Ketamine Current Psychopharmacology, 2019, Vol. 8, No. 2 3

intravenous ketamine infusion altered neuroplasticity-related proteins in the hippocampus, amygdala, and the prefrontal cortex.

2.1. The Anti-Depressant Effects of Ketamine: Clinical Observations

Ketamine is considered a significant break-through in the field of treatment for refractory de-pression [6]. Many recent studies looked at the ef-ficacy of ketamine for the treatment of Major Dep- ressive Disorder (MDD) and Suicidal Ideation (SI).

In support of the anti-depressant effects of ket-amine, Reed et al., [7] used functional magnetic resonance imaging (fMRI) emotion-based atten-tional task for a placebo-controlled, crossover study of 33 un-medicated participants with MDD and 26 healthy controls (HCs). In MDD, brain ac-tivity post-ketamine was similar to healthy con-trols post-placebo. These findings suggest that ket-amine may act by normalizing brain function in depressed individuals.

Caddy et al. [8] reviewed the use of glutamate receptor modulators in unipolar depression. Among all glutamate receptor modulators, only ketamine (administered intravenously) proved to be more efficacious than placebo, although limita-tions included small sample sizes and risk of bias. There was low quality evidence that treatment with ketamine increased the likelihood of response after 24 hours (odds ratio (OR) 10.77, 95% confi-dence interval (CI) 2.00 to 58.00; 3 RCTs, 56 par-ticipants), 72 hours (OR 12.59, 95% CI 2.38 to 66.73; 3 RCTs, 56 participants), and one week (OR 2.58, 95% CI 1.08 to 6.16; 4 RCTs, 131 par-ticipants). The effect of ketamine was even less likely at two weeks, as data were available from only one trial (OR 0.93, 95% CI 0.31 to 2.83; 51 participants, low-quality evidence). Compared to the placebo, ketamine caused more confusion and emotional blunting [7].

Grady et al. [9] reviewed seven randomized controlled trials of ketamine usage in major de-pressive disorder and bipolar depression. They found that ketamine demonstrated a statistically significant improvement over placebo or midazo-lam in MDD and bipolar depression and suggested that ketamine may be helpful for patients that have exhausted other therapeutic options.

Ballard et al. [10] pointed out that until the glu-tamatergic modulator ketamine was found to elicit rapid changes in active suicide-ideation (SI), no pharmacological treatments existed. They evaluat-ed clinical, demographic, and neurobiological fac-tors from data pooled from five clinical ketamine trials. Treatment-resistant inpatients (n=128) with DSM-IV-TR-diagnosed MDD or bipolar depres-sion received one sub-anesthetic (0.5mg/kg) keta-mine infusion over 40 min. Growth mixture mod-eling generated the SI response classes used to an-alyze composite SI variable scores, and multino-mial logistic regression was used to evaluate class membership predictors. They found that response only extends to Day 3. Plasma markers were used rather than cerebrospinal fluid (CSF) markers. The heterogenic response to ketamine of those with SI underscores its potential independence from changes in a depressed mood. Individuals report-ing symptoms that suggested a longstanding histo-ry of chronic SI were less likely to respond or re-mit post-ketamine.

Ren et al. [11] evaluated the use of ketamine in electroconvulsive therapy ECT for depressive dis-order in a systematic review and performed a meta-analysis of sixteen studies, including 928 pa-tients. They found that at the end of six ECTs, no significant standardized mean difference (SMD) was observed in favor of the ketamine group, alt-hough depressive scores were lower in the keta-mine group after 1st ECT and 3rd to 6th ECTs. They found that while ketamine used in ECT can-not reduce the depressive symptoms at the end of treatment, it could accelerate the anti-depressive effect in depressive patients receiving ECT, espe-cially in those who used ketamine as an add-on anesthetic. However, adverse events were in-creased, primarily related to cardiovascular and psychiatric systems, during the whole ECT course.

Sinyor et al. [12] used a case series of five in-patients admitted to a tertiary care hospital for six serial ketamine infusions to explore ketamine augmentation for MDD and SI in a real-world in-patient setting. The standard 0.5mg/kg intravenous (IV) ketamine was used for about two weeks and evaluated using suicide and depression rating scores; Scale for SI and the Montgomery-Asberg Depression Rating Scale, (MADRS) at baseline and on treatment days. They found that all patients


experienced benefit with ketamine. In terms of SI scores, they diminished by 84% from 14.0+/-4.5 at baseline to 2.2+/-2.5 at study endpoint. The MADRS scores decreased by 47% from 42.2+/-5.3 at baseline to 22.4+/-8.0. One patient withdrew from the study to initiate ECT, and another due to dissociative effects during the ketamine infusion. They suggest that these preliminary pilot data are promising with a more than two-fold reduction in SI following ketamine infusions and large-scale randomized controlled trials to confirm the effica-cy of serial ketamine for the treatment of SI in "re-al-world" settings.

In a randomized, double-blind, placebo-controlled trial, Ionescu et al. [13] reported on twenty-six medicated outpatients with Severe Major Depres-sive Disorder (SMDD) and current, and chronic SI randomized to saline placebo or six ketamine infu-sions (0.5mg/kg over 45 minutes) over three weeks. Depression and SI assessments were made at baseline, 4 hours post-infusion, and during a three-month follow-up phase. During the infusion phase, there were no differences in depression se-verity or SI between placebo and ketamine was seen (p=0.47 and p=0.32, respectively). By the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission from depression. The three-month fol-low-up yielded two patients in each group who met the criteria for remission from depression. Uncontrolled outpatient medication regimens, the small sample size, and the restriction to outpa-tients, who may have had lower levels of SI than would be seen in emergency or inpatient settings, were limitations of this study. In this double-blind, placebo-controlled study, non-escalating repeated doses of ketamine did not outperform placebo for patients with severe TRD and current, chronic SI. The commonly used dose of 0.5mg/kg from previ-ously published open-label data was not sufficient in this severe and chronically ill outpatient popula-tion.

3. THE MONOAMINE HYPOTHESIS OF DEPRESSION

Importantly, the impact of conventional antide-pressants on clinical symptoms, are thought to be due to increasing the availability of amine neuro-transmitters. The full antidepressant response takes

weeks of daily administration; some patients do not respond adequately. Moreover, the lack of ad-equate immediate response is a crucial limitation of antidepressant therapy because this prolonged time to act results in a lack of medication compli-ance, difficulty switching medications, and the risk of suicide [2, 14]. These phenomena highlight an urgent need for new drugs with higher response rates and a rapid onset of action. ketamine at low doses, unlike typical antidepressants, has been shown in clinical trials to induce a rapid, although short-lived anti-suicide and anti-depressant effect.

In summary, the fMRI study found that com-pared to placebo, post-infusion, Ketamine normal-izes brain function in depressed individuals. The studies also evaluated the efficiency of standard doses, dosing protocols, and Ketamine in combi-nation with ECT and medication. However, the outcomes measured in the length of symptom re-mission are mixed. A better understanding of the mechanism of action (MOA) of Ketamine and pro-longing the antidepressant effects would be worthwhile goals.

A focused review of the use of glutamate recep-tor modulators in unipolar depression from Caddy et al. [8] found ketamine to be effective compared to placebo at time points up to one week, with less certain effects at two weeks post-treatment.

4. PHARMACOGENETICS OF KETAMINE Clinical evidence about the metabolism of ket-

amine to norketamine was used by Li et al. [15] to explore the pharmacogenetics of ketamine. He found that the presence of the CYP2B6*6 allele variant of the CYP2B6 genotype might explain the 60-80 percent inter-individual variability of plas-ma ketamine concentrations. In chronic pain pa-tients, the CYP2B6*6 allele associated with a sub-stantial decrease in steady-state ketamine plasma clearance that resulted in higher plasma concentra-tions and may result in higher ketamine adverse effects. Other influences on ketamine plasma con-centrations include age and other challenging to quantify influences, such as pro-anti-inflammatory effects and opioid-induced hyperalgesia. Age-related change, possibly due to decreased blood flow to the liver, might account for 20 to 30 per-cent of the differences in ketamine plasma clear-ance.


Moaddel et al. [6] explored the plasma to pro-file ketamine and placebo in a crossover trial of treatment-resistant major depressive disorder (n=29) healthy control subjects (HCs) (n=25). They found that ketamine treatment resulted in a general in-crease in circulating sphingomyelins levels, with-out a correlation to response to ketamine. Howev-er, in the kynurenine and the arginine pathways at four hours post-infusion, more pronounced effects were observed. Circulating kynurenine levels de-creased, and the bioavailability of arginine in-creased in responders to ketamine treatment. Argi-nine is an α-amino acid that is used in the biosyn-thesis of proteins and is the precursor for the bio-synthesis of nitric oxide (NO), suggesting NO as a possible mechanism for response to ketamine.

5. UNDERSTANDING THE NEGATIVE EF-FECTS KETAMINE: STILL A MYSTERY

David Olsen [4] pointed out that the risks asso-ciated with using these drugs that are capable of profoundly impacting the neuronal structure are unknown. The promotion of neuronal growth dur-ing development could interfere with the normal processes which refine neural circuits. Equally, the effects psychoplastogens will have on the aging brain like mTOR activation, are unclear. Excessive mTOR activation is associated with some diseases, including autism spectrum disorder and Alz-heimer’s disease.

The therapeutic benefit of ketamine, while use-ful for those with TRD, has thus far been short-lived. The neurotoxic effects and the potential for abuse suggest that the use of ketamine in a clinical setting warrants further investigation. Develop-ment of new and improved drugs or protocols that retain the antidepressant effects and avoid issues like the mechanism-related dissociative side-effects of ketamine (or esketamine), and explore the route of administration are needed [16, 17].

Moreton et al. investigated the abuse potential of ketamine in rhesus monkeys. They worked with self-administration behavior daily for 2-hours. That the data showed that ketamine maintains self-administration behavior like that of some other drugs and conventional reinforcers [18]. The dis-sociation and delirium effects of ketamine have led to recreational abuse, which puts users at risk of environmental harms like nonconsensual sexual

intercourse. Chronic ketamine use may lead to memory impairment of and persistent dissociative, depressive, and delusional thinking. Also, lower urinary tract infections, including cystitis and gas-tric and hepatic pathology; abnormal liver function tests, choledochal cysts, and dilations of the com-mon bile duct, have been reported [19].

6. THE SEARCH FOR THE MECHANISM OF ACTION OF KETAMINE: WHY IS THE ANTIDEPRESSANT ACTIVITY SO SHORT LIVED?

Chronic depression causes atrophy of the neu-rons in the Prefrontal Cortex (PFC), a region of the brain that controls anxiety and regulates mood. The branches and spines shrivel up and disconnect from other neurons. One hypothesis about why ketamine is useful is that it can rapidly regrow the arbors and spines of these critical neurons.

Studies from Olson’s group [4] at UC Davis of neurons grown in dishes, and experiments using rodents and fruit flies, demonstrated that several psychoplastogens, like psychedelics and ketamine, activate the mammalian target of rapamycin (mTOR); a protein an essential in cell growth that encourages neuronal proliferation of more branch-es and spines [4]. Importantly, this does not ex-plain why the antidepressant effect is so transient when the growth of PFC atrophic neurons is induced by ketamine [20]? Also, Grady et al. [9] suggested that ketamine exerts its antidepressant properties through N-methyl-D-aspartate (NMDA) receptor antagonism.

Witkin et al., reviewed the literature in 2018 [20] found that a documented extracellular gluta-mate efflux is induced by these drugs, and hypoth-esized that the triggering mechanism is excitatory neurotransmission produced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor amplification.

Further, Lur et al. [21] found that four hours af-ter ketamine treatment, glutamatergic synapses themselves are not significantly affected. Howev-er, they reported that the loss of Regulator of G-protein Signaling (RGS4) activity might be due to the disruption of synaptic modulation through a very complicated neuromodulatory mechanism. It is known that under control conditions, α2 adren-


ergic receptors and type B γ-aminobutyric acid (GABAB) receptors selectively inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AM-PA) -type glutamate receptors (AMPARs) and NMDARs, respectively. If the GABA inhibitory activity is interrupted by ketamine through the above mechanism, would this dis-inhibition drive dopaminergic release at the VTA-NAc? The diffi-culty is to understand why following ketamine in-fusion and reduction in RGS4 activity, via the mechanism observed by Lur et al. [21], the resultant disinhibition of glutaminergic transmission induced anti-depressant response in TRD is short-lived.

Thus, the suggestion has been that ketamine’s short-acting anti-depressant effect may in part be due to GABAergic activity. While a thorough search in the literature reveals several theories with some evidence, the foremost studies seem contradictory. Boczek et al. [22] reported that fol-lowing a 5-day infusion of subanesthetic doses to rats; post-mortem analysis revealed diminished GAD67 expression in the cortex of the cerebellum (by ∼60%) and in the hippocampus (by ∼40%) that correlated with lowered protein level in these areas. The expression of GAD65 isoform decree- sed by ∼45% in the striatum, but a pronounced ∼90% increase was observed in the hippocampus. Consecutively, reduction in glutamate decarbox-ylase activity and GABA concentration was detected in cortex, cerebellum, and striatum, but not in the hippocampus. Ketamine administration decreased GABA transaminase protein in cortex and striatum (by ∼50% and 30%, respectively), which was reflected in the diminished activity of the enzyme. They also observed synaptic GABA release to be reduced by ∼30% from striatal termi-nals. In terms of the inhibitory role of reducing glutaminergic drive, lowered GABA activity could help explain the subsequent increase of NAc do-pamine release and ketamine’s anti-depressant ef-fects.

Magnetic resonance spectroscopy data, recently supported evidence available since 1980, suggest-ing that central nervous system GABA concentra-tions in major depressive disorder (MDD) patients are reduced, leading to the assumption that the un-derlying etiology MDD's maybe an overall reduc-tion in GABA-mediated inhibitory neurotransmis-sion. Along these lines, albeit not in agreement,

Fuchs et al. [23] found that loss of inhibitory syn-aptic input resulted in increased excitability of SST+ interneurons (somatostatin-positive GA-BAergic interneurons). Increased frequency of spontaneous inhibitory postsynaptic currents py-ramidal cell targets of SST+ neurons was ob-served. Enhanced GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells resulting in chronic reductions in the synaptic ex-citation- inhibition-ratio and represents a novel strategy for antidepressant therapies that reproduc-es behavioral and biochemical endpoints of rapidly acting antidepressants like ketamine. New theories suggest that higher brain concentrations of gluta-mate (excitatory) and lower GABAergic interneu-ron input (inhibitory) promote depression. In terms of understanding related mechanisms of antide-pressant effects, the conclusion that increasing glu-taminergic drive by reducing inhibitory control through GABA induces depression, in fact, using this logic, the opposite would be expected. Pehr-son and Sanchez [24] strongly argue that the con-siderable gaps in comprehension of the relation-ship between MMD and GABA physiology, must be corrected with new data from well-controlled empirical studies. The conclusion, of their review, suggests that the hypothesis that MDD is caused by reduced GABA neurotransmission is too sim-plistic and a more nuanced and complex model of the role of inhibitory neurotransmission in MDD is needed.

Although these newer views of the causes of MDD seem counterintuitive, they are not. The idea that sustained GABAergic transmission results in disinhibition of GABAergic interneurons that in-crease frequency of spontaneous inhibitory postsynaptic currents resulting in chronic reductions in the synaptic excitation- inhibition-ratio, reduces depression supporting the earlier view of the mon-oamine hypothesis of depression; that reduced do-pamine at brain reward sites is described as the primary cause of depressive symptoms [25, 26]. The sustainability of the antidepressant effect of ketamine may reside in the sustainability of the GABAergic transmission via ketamine infusion.

Beluion & Grace [25] suggest that anhedonia is an essential aspect of depression, and while dopa-minergic activity is complicated, its dysregulation leads to MDD. They point out that dopaminergic


activity is under the regulation of multiple brain structures, such as the ventral subiculum of the hippocampus and the basolateral amygdala. How-ever, whereas basic and clinical studies demon-strate deficits of the dopaminergic system in de-pression, to further understand not only specific therapeutic targets of ketamine, the origin of these deficits may lie in dysregulation of its regulatory afferent circuits. The newer view involving disin-hibition of somatostatin-positive GABAergic in-terneurons that results in an anxiolytic and antide-pressant-like brain state represents a new oppor-tunity to target GABAergic interneurons for the treatment of TRD that could increase the effect duration while maintaining the rapid effect of treatment.

The rationale related to Glutamate/GABA ex-citatory /inhibitory ratios and ketamine’s anti-depressant short-term effects, is presented in a brief snapshot of the currently available data which seems prudent, but additional research is required to help dissect the complex nature of this important interaction. The older view of neuro-chemical correlates of depressive symptoms was tied to serotonergic and dopaminergic balance and not GABA or glutamate [27], however, more re-cently, others [28, 29] based on analyses of de-pressed patients have found new evidence of re-duced expression of plasma membrane glutamate transporters, and elevated brain concentrations of glutamate [30]. Therefore, in several studies, MDD is associated with attenuated GABAergic activity including reduced GABA concentrations [31-36]; decreased expression of GABA type A receptors (GABAARs) [37]; lower expression of glutamic -acid decarboxylase [38, 39]; and dys-function of GABA type interneurons [40-42]. Moreover, chronic and high stress lead to impaired inhibition of neural pathways by chloride reversal potential of neurons, rendering GABA ineffective as an inhibitory neurotransmitter. This effect is found in the paraventricular nucleus of the hypo-thalamus that modulates the stress axis, as well as the hippocampus [43-45]. Importantly, cellular vulnerability to stress is augmented in a subclass of GABAergic interneurons that express the neu-ropeptide somatostatin (SST) [46]. In response to stress, the excitatory/inhibitory imbalances over-come by reciprocal positive reinforcement, and this mechanism has been implicated in MDD.

Recently, Liston and associates [47] reported in Science (2019) that they might have found a bio- logical reason for neuronal changes underlying depression-related behaviors in mice. NIH researchers used high-resolution images of dendritic spines in the prefrontal cortex, before, and after mice experienced stress, to explore mechanisms underlying the transition from active depression to remission in humans. The researchers found the decreased formation of, dendritic spines, (protru- sions that receive input from other neurons) in their prefrontal cortex, and increased behaviors related to depression in the stressed mice compared to non stressed mice.

Reduced resting-state functional connectivity (rsFC) and replicated studies link the emergence of depressive behaviors in mice with dendritic spine loss. Striatal dopamine deficits predicted reduced striatal functional-connectivity in major depression, as seen in concurrent 11C-raclopride positron emission tomography and fMRI investigation. Hamilton et al. [48] and Liston’s group [45] found that treatment with ketamine quickly restored functional connectivity and of neuronal assembly eliminating depression based behaviors in mice. Mice exposed to stress showed a reversal of behaviors related to depression twenty-four hours after receiving one dose of ketamine. Also, dendritic-spine formation increased compared to stressed mice that had not received ketamine. While this work could help explain the neuronal reversal of stress-induced dendritic changes in mice, and in humans, reduced rsFC has also been linked to low dopamine function, and as such depressive symptoms, the concern here is that linking human depression to mice may be problematic and must await further human-based testing.

It is current thinking that normalization of the GABA/Glutamate ratio should be the preferred therapeutic target supported by a series of studies involving anti-depressant and electroconvulsive therapy of depressed patients [49-52]. Also, Shen et al. [49] reported that reduced function of GABAARs (GABAAR γ2+/− mice) results in anxious-depressive-like phenotypes of mice that are normalized by chronic treatment with antidepressant drugs, such as the tricyclic desipramine. Remarkably, Ren et al. [53] showed that ketamine, normalizes the depressive-like phenotypes of


GABAAR γ2+/− mice, by potentiating the medial PFC inhibitory synapses. Currently, it appears that ketamine’s rapid, but short-lived anti-depressant effect, may be due to a number of complex mechanisms including 1) promoting the formation and function of synapses [53, 54]; 2) triggering a cascade of phosphorylation events 3) activating target of rapamycin (mTOR) 4) activation of p70S6K (S6K); 5) inhibition of factor 3 kinase (eEF2K); 6) attenuation of inhibitory phosphorylation of the single eEF2K target, eEF2; 7) augmented activity of eEF2 and increased mRNA translation elongation [55, 56] and 8) possible increased dendritic mRNA translation elongation [57-74].

It is noteworthy that defects in GABAergic synaptic transmission significantly improve the antidepressant response to ketamine. However, as suggested by others [75], none of these data demonstrate a causative relationship between enhanced GABAergic synaptic transmission and effective antidepressant therapies.

However, Newport et al. [76] conducted a systematic review and meta-analysis of ketamine and other NMDA receptor antagonists for the treatment of major depression. They searched MEDLINE, PsycINFO, and other databases for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Importantly, in terms of NMDA antagonists, the rates of treatment response and transient remission of symptoms, as well as changes in the frequency and severity of dissociative psychotomimetic effects, and depression symptom severity were subse- quently measured. From seven trials of n=147 ketamine-treated participants, they found that ketamine produced a rapid, yet transient, antidepressant effect accompanied by brief psychotomimetic and dissociative effects. From five trials of total n=89, Ketamine augmentation of electroconvulsive therapy (ECT) significantly reduced depressive symptoms following initial treatment, but not after the ECT course. Other NMDA antagonists failed to demonstrate efficacy consistently. However, two partial agonists at the NMDA co-agonist site, rapastinel and d-cycloserine, significantly reduced depressive symptoms without psychotomimetic or dissociative effects [76]. This positive effect of partial agonism of NMDA makes

sense is supported by older theories of depression linked to dopamine function.

The failure of other NMDA antagonists sug-gests that any future advances will depend on im-proving understanding of ketamine's mechanism of action [3]. Krystal’s group recently showed in a small case series of five patients, that Ketamine’s antidepressant effect was not attenuated with nal-trexone pre-treatment. The lack of effect attenua-tion is noteworthy because it argues against other work suggesting that ketamine’s antidepressant effect in MDD is due to opioid receptor stimula-tion as well as increased Global Brain Connectivi-ty in the lateral PFC, caudate, and insula [77]. Pos-sibly, blocking NMDA receptors could induce a reduction in glutaminergic drive at the VTA, caus-ing a reduced Dopamine (DA) release at NAc. In-deed, NMDA antagonism does not lead to proper dopamine function and therefore should not lead to antidepressant activity. Therefore, agonism of NMDA does perhaps make more sense.

6.1. What About Dopamine? Kokkinou et al. [78] proposed a mechanism of

action for ketamine in influencing dopamine’s change from baseline. Accordingly, Ketamine blocks NMDA receptors on GABAergic interneu-rons disinhibiting glutamate neurons projecting to dopamine neurons in the midbrain, augmenting glutamate release resulting in enhanced dopamine neuronal firing and as such increasing dopamine levels in the striatum and cortex of rodents. A me-ta-analysis involving 40 original peer-reviewed studies provided evidence for the role of dopamine in ketamine’s antidepressant effects. Even in sev-eral rodent investigations, acute ketamine admin-istration significantly enhanced dopamine levels in the cortex, striatum, and the NAc. Compared to controls, ketamine induced a 62-180% increase in dopamine neuron population firing. With chronic ketamine administration, they found cortical do-pamine release to be from 88-180%. Of interest is the fact that sub-anesthetic doses of Ketamine in healthy humans acutely produces symptoms simi-lar to schizophrenia [79] and low-level schizo-phrenic symptoms are seen in ketamine abusers [80].

Moreover, ketamine exacerbates psychotic symptoms in patients with known schizophrenia


[81]. To reiterate, Peciña et al. [27] reported that compared to controls, patients with depression had greater D2/3 receptor availability in several striatal regions, such as bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. Moreover, the depressed group, D2/3 receptor availability in the caudal por-tion of the ventral striatum vPAL NAc correlated with higher anxiety symptoms. However, D2/3 receptor availability in the rostral area of the ven-tral striatum correlated negatively with the severity of motivational anhedonia. Importantly, MDD non-remitters showed greater baseline anxiety, greater D2/3 availability in the vPAL/NAc, and greater placebo-induced DA release in the bilateral NAc. Higher availability D2/3 receptors in the ventral striatum of patients with MDD seems to be associated with lack of response to antidepressants and comorbid anxiety symptoms, an important in

consideration of the antidepressant effect of keta-mine in TRD. It is noteworthy that higher D2/D3 receptor availability means lower dopamine re-lease and as such a hyperdopaminergic exists caus-ing MDD symptoms.

The work of Hare et al. [82] offers further sup-port for the role of dopaminergic function in keta-mine’s anti-depressant effect. Using optogenetic stimulation of medial prefrontal cortex DRD1 neu-rons similar to ketamine stimulation induces a rap-id anti-depressant effect. However, unlike keta-mine, this anti-depressant effect was long-lasting. Also, disruption of DRD1 neuronal firing blocked the rapid antidepressant effects of ketamine. These results suggest that downstream- anti-depressant effects of ketamine, independent of mechanism [83-95] seem to involve dopaminergic activity (Fig. 1).

Fig. (1). Illustrates dopamine receptor modulation through epigenetic neuroadaptation via D1/D2 antagonism, also, D2/D3 availability in the ketamine therapeutic action has a notable role in the ketamine mechanism. Depression results from attenuation of dopamine at the reward sites, but ketamine increases dopamine activity at the reward site. Also, ketamine induces a lowering of the availability of D2/D3 receptors by actually augmenting DA neuronal release at the Ventral Tegmental Area (VTA) - N. Accumbens (VTA-NAc). This effect of Ketamine provides at least one antidepressant mechanism. Also, the α2 adrenergic receptors, and type B γ-aminobutyric acid (GABAB) receptors selectively inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate re-ceptors (AMPARs) and NMDARs. Thus, respectively if the GABA inhibitory activity is interrupted, this dis-inhibition drives dopaminergic release at the VTA-NAc, which in the end increases the activity of the reward cycle and decreases depression.


Dopamine involvement in proposed mecha-nisms of ketamine action and its role as an antide-pressant. Fig. (1).

7. SUMMARY

Ketamine, a known Psychoplastogens capable of rapidly promoting structural and functional neu-ral plasticity, is effective in TRD with a short-term effect [19, 96-99]. Recent studies in humans have suggested both an important role for endogenous opioids and opioid-like effects in ketamine’s anti-depressant effect [100-102]. However, with thou-sands of studies published on this topic, the exact mechanism of ketamine as a rapid anti-depressant remains unknown.

It is noteworthy that ketamine’s proposed an-tagonistic activity of NMDA receptors as a way of explaining ketamine’s anti-depressant effect, seems counter-intuitive, and as such, we have ar-gued this proposed mechanism, as evidenced from the work of Newport [76]. Additionally, the role of ketamine’s opioid receptor stimulant effects has also been adequately refuted [101]. It has not clearly been shown that the rapid effect of keta-mine is due to enhanced dopaminergic function, which seems most likely in the face of a large body of literature, including studies on genetics related to depression and dopaminergic function [103-105]. However, its role as anti-depressant may be revealed by using newer techniques like optogenetics [82]. One important caveat is the suggestion that dopamine plays a significant role in ketamine’s antidepressant effect requiring more in-depth human rather than animal studies.

CONCLUSION

The clinical findings presented here, concern prolonging ketamine’s effects and require addi-tional investigation. Scientific and clinical col-leagues are urged to perform more extensive con-trolled experiments in humans to test these thought-provoking new theories. While in terms of ketamine’s effects on neural circuits, especially in animals, advances have been made in terms of ex-plaining potential mechanisms concerned with the known rapid anti-depressant effects requiring cau-tion until human data is executed. To date, there are 26 articles listed in PUBMED (3-22-19) using

the search terms ketamine, depression, and fMRI in humans. However, currently, no definitive con-clusions can be extracted from these sophisticated studies and future human studies will be required to determine ketamine’s neurochemical mechanism [102] and to avoid the addictive and dissociative side-effects. Development of new and improved drugs that retain the rapid antidepressant effects but are devoid of the issues associated with ketamine itself relies on understanding the MOA and development of new methods of drug delivery.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

KB is the recipients of R41 MD012318/NIMHD NIH HHS/United States.

CONFLICT OF INTEREST

Kalypso Wellness Centers of San Antonio, Texas, has developed several ketamine related pro-tocols currently commercialized, and the following individuals have stock in the company: BC, CC, SW, and EC. TP is a consultant, and MM is a con-sultant paid by Kalypso. There are no other con-flicts of interest for KB, DB, LL, BB, MSG.

ACKNOWLEDGEMENTS

The authors appreciate the staff of Geneus Health LLC., especially Justin Jones and Erin Gallagher, and Jessica -Valdez Ponce.

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