Unconventional Neuropharmacology: Ketamine
Image Unavailable

Image courtesy of Journeys in Wonderland Blog [23]

Psychiatric disorders and mental illness are prevalent concerns in today’s society. The heterogeneity of disorders such as depression has made it difficult to pinpoint their exact causes and has thus made it difficult to develop successful treatments. Viable therapeutic options such as the advent of antidepressants have shown some promise in alleviating affective symptoms of depression; however, despite being consistently refined and improved, they are still, at best, only 30-40% effective. Presently, there is an alarming demand to explore alternative methods of treatment, as the rates of mental illness are staggeringly high, with as many as one third to one half of individuals experiencing at least one depressive episode in a lifetime[1]. As such, scientists have revisited the idea of unconventional therapeutic approaches, including the use of illicit drugs such as psilocybin mushrooms and ketamine, which play a role in neural pathways involved in the regulation of affect and reward. Renewed interest and research into these drugs provides promise to individuals who, having exhausted all other therapeutic options, feel hopeless with the little success that conventional treatments have provided[2].

1. Depression Overview

1.1 Symptoms

Depression is a common debilitating psychological disorder with the highest burden of disease in Canada and the United States, with detrimental economical and societal implications. It is estimated that as much as 10% of Americans are plagued by major depressive disorder[3]. Some common symptoms associated with depression include changes in weight; extreme fatigue and loss of energy; thoughts of death or suicide; irritable or sad mood; feelings of worthlessness; guilt, and helplessness; the inability to concentrate; impaired memory; and anhedonia, the inability to experience pleasure. These symptoms can have a profound effect on individuals’ lives because they interfere with everyday functioning, often preventing people from attending to social responsibilities, such as their job, school, and interpersonal relationships[4].

1.2 Treatments

Some treatments for depression involve psychotherapy (talk therapy), electroconvulsive therapy (ECT), deep brain stimulation (DBS), and cognitive behavioural therapy. While ECT has been shown to be quite effective in alleviating most symptoms of depression, it remains controversial because of its potential to cause cognitive impairment and memory loss. The most commonly used treatment for depression is antidepressant medications (ADMs), such as selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. However, ADMs are effective in only 30-40% of individuals and, if successful, their antidepressant effects take several weeks to manifest[5]. In fact, depression is considered to be treatment resistant once individuals have tried two or more typical ADMs with no success or symptom alleviation[6]. These therapies are largely based on the monoamine hypothesis, which posits that individuals deprived of monoamines will exhibit symptoms of depression so increasing levels of key neurotransmitters such as serotonin and noradrenaline in specific brain regions should alleviate depression. However, the limited efficacy of ADMs suggests that other neurological pathways and mechanisms are involved in depression[5]. As such, researchers have begun looking into other possible treatments for depression such as the use of unconventional drugs like ketamine and psilocybin mushrooms because of their apparently immediate antidepressant effects[6].

2. Ketamine Overview

2.1 Background

Molecular Structure of Ketamine

Image Unavailable

Image courtesy of Wikipedia [22]

Space-Filling Model of Ketamine

Image Unavailable

Image courtesy of Wikipedia [22]

Calvin Stevens, a scientist at the Parke-Davis Laboratories in America, first synthesized Ketamine in 1962. Ketamine was initially developed as a replacement anesthetic for phencyclidine (PCP), which was deemed too dangerous for use in the medical relief of American soldiers during the Vietnam War due to its severe refractory hallucinogenic effects. However, in the 1970s, the recreational use of ketamine emerged in Western America, as it was accessible and relatively inexpensive. It quickly gained popularity as a popular rave drug throughout the world, likely because of its reported ability to produce pleasurable mind-body dissociation in the user. In 2005, ketamine was classified as a Schedule I narcotic according to the Controlled Drugs and Substances Act of Canada and is only legal for use by health care professional and for regulated research. Currently, ketamine is primarily used as an anesthetic in veterinary medicine; however, it has limited utility in human medicine as an anesthetic in specific surgical contexts[7].

2.2 Side Effects

Ketamine is considered an analgesic, meaning that it is both an anesthetic and a hallucinogen.
Side effects of ketamine are largely dose dependent. Low doses, such as those used in human medical contexts, as well as doses used in current research on ketamine’s antidepressant effects, are unlikely to produce profound and prolonged altered states of consciousness. However, at larger doses, such as the quantities of powdered ketamine inhaled or snorted of in those that abuse the drug, there are severe psychological and physical repercussions. Some individuals report a pleasurable experience, a state of altered consciousness that is often referred to as a k-hole in partying contexts. The K-hole is described as involving feelings of euphoria, sensations of disembodiment, and loss of temporal and spatial perception[7][1]. Set and setting play a significant role in an individual’s response to hallucinogenic drugs, including ketamine[8]. If a person is not in the correct mindset or is not in a supportive context, hallucinogens such as ketamine can produce a psychologically traumatizing experience, more commonly referred to as a “bad trip.” This can include extreme fear and paranoia[9]. Although ketamine has a wide margin of safety when it comes to dose, it can cause cognitive impairment, increased risk for cardiovascular complications, kidney dysfunction, and psychosis. Furthermore, it has addictive properties, with frequent users reporting symptoms of withdrawal upon cessation of use, as well as an effect of tolerance with regular use[7].

2.3 Mechanism of Action

Mechanism of Action

Image Unavailable

Ketamine-mediated NMDA receptor antagonism and glutamate release[1].

Ketamine, 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone or CI581, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The neurobiology of ketamine is not yet fully understood; however it has been widely proposed that ketamine’s primary mechanism of action involves the glutamatergic system. Ketamine binds to the phencyclidine site in the ionotropic channel of NMDA receptors, which blocks the activity of GABA-ergic interneurons in both subcortical and cortical areas of the brain. Subsequently, the firing rate of excitatory glutamatergic neurons occurs, resulting in a substantial increase in the presynaptic release of glutamate. Simultaneously, ketamine causes a blockade of NMDA receptors on pyramidal neurons in the cortex. The resulting transient surge, or flooding, of glutamate in the synaptic cleft leads to a relative increase in AMPA receptor activity compared to NMDA receptor activity due to ketamine’s blocking effect[1].
In turn, there is an increase in AMPA receptor-mediated downstream effects, such as the ultimate expression of brain-derived neurotrophic factor (BDNF) and activation of the mammalian target of rapamycin (mTOR)[10]. Overall, ketamine’s antagonistic effects on the NMDA receptor, as well as the simultaneous presynaptic release of glutamate and subsequent heightened AMPA receptor activity are the mechanisms proposed to underlie ketamine’s rapid effects as an antidepressant[1].

3. Ketamine in Depression

Ketamine as a Possible Antidepressant

The Doctors discuss the potential therapeutic effect of ketamine as an antidepressant. Video courtesy of You Tube [24]

3.1 First Controlled Study for Treatment of Depression

Carlos Zarate and his colleagues at the National Institute of Mental Health conducted the first controlled study of ketamine for the treatment of depression in 2006. Frustrated with the delayed temporal efficacy of traditional typical antidepressants, researchers wanted to see if an NMDA antagonist, specifically ketamine, would achieve more rapid antidepressant effects in subjects with major depression. Extensive inclusion criteria need to be met for participants to take part in the study, including the absence of any psychotic features outlined in the DSM-IV. In addition, participants were required to have had previous lack of success with at least two typical antidepressants and no history of alcohol or substance abuse. Ketamine was intravenously administered to 17 patients and the 21-item Hamilton Depression Rating Scale was measured changes in depressive symptoms at various time points (40, 80, 110, and 230 minutes post-infusion, and 1, 2, 3, and 7 days post-infusion). Results indicated that a single dose of ketamine led to a 50% reduction in depressive symptoms in half of the patients within only two hours of administration, whereas similar response rates take up to eight weeks to see with the use of typical antidepressants such as selective serotonin reuptake inhibitors. In addition, 71% of patients showed a significant reduction in symptoms after the first day post-infusion. Although about a third of the patients reported continued relief a week after treatment, this highlights one of the potential limitations of ketamine as therapy in that it’s effects are relatively short-lived, indicating that frequent injections might be required[11]. It is important to note, however, that the expected half-life of ketamine in humans is about three hours, yet its antidepressant effects continue to persist well after it has been fully metabolized[12]. Overall, this study was integral to research regarding new therapeutic avenues for the treatment of depression because it paved the way for further studies to be done exploring the beneficial effects of psychedelic drugs[11].

3.2 Other Noteworthy Research

3.2a The Role of Ketamine in the mTOR Signaling Pathway

Recent findings suggest that mammalian target of rapamycin (mTOR) and its associated pathway is a downstream target of ketamine. mTOR is a serine/threonine protein kinase that has a plethora of functions including the regulation of cell proliferation, cell survival, cell growth, and transcription[13]. Synaptic dysfunction in various areas of the brain including the prefrontal cortex (PFC) and hippocampus has been implicated in numerous cases of depression, both in animals and humans[14]. After conducting a series of experiments, researchers found that administering ketamine to rats led to a transient, two hour-lasting increase in phosphorylation and activation of mTOR in the prefrontal cortex. In addition there was increased phosphorylation of upstream growth factor signaling pathways, such as the protein kinase B and extracellular-signal regulated kinase (ERK) pathways, which ultimately lead to mTOR pathway activation as well. However, antidepressants, such as fluoxetine did not show the same effect of mTOR activation. Furthermore, in a second experiment, researchers applied an AMPA receptor inhibitor prior to the administration of ketamine and found that levels of phosphorylated mTOR and ERK pathways were no different from controls, suggesting that ketamine’s mechanism of action occurs, at least in part, through increased AMPA receptor activity[((bib cite 13))][14]. Furthermore, using two-photon imaging, ketamine was found to increase the levels of certain synaptic proteins, such as postsynaptic density 95 (PSD95), synapsin I, and glutamate receptor 1 (GlurR1). Imaging also revealed a rapid increase in synaptogenesis, in addition to an increase in size and density of dendritic spines in the PFC. This synaptic strengthening was verified by an increase in excitatory postsynaptic currents after the application of serotonin to slices of the PFC from rats treated with ketamine. Finally, a different experiment in the same rats looked at the behavioral effects of ketamine in various chronic unpredictable stress models in rats, including the forced swim test (FST), the novelty suppressed feeding test (NSFT), and learned helplessness in response to inescapable stress. Rats given a single ketamine injection showed an immediate reduction (within 24 hours of being injected) of depressive symptoms for all three tests. In order to verify if this reduction was the result of ketamine-induced mTOR signaling, researchers infused some rats with rapamycin, an mTOR kinase inhibitor, into the medial prefrontal cortex. Rapamycin blocked mTOR signaling in mice injected with ketamine, as evidenced by the reversal of any reduction in depressive symptoms in the NSFT and FST tests. This suggests that ketamine does in fact play a role in mTOR-dependent synapse formation and the resulting antidepressant effects of these important downstream signaling pathways[13]. Other studies have shown similar results in human subjects using magnetoencephalographic recordings that measured synaptic potentiation pre- and post-ketamine infusions and corresponding antidepressant measures such as the Montgomery-Asberg Depression Rating Scale (MADRS)[15].

Intracellular Processes Activated by Ketamine

Image Unavailable

Prefrontal cortical activation of synaptic processes and signaling pathways involving BDNF and mTOR as a result of ketamine infusion[21].

3.2b The Association between Ketamine and BDNF

Another significant study highlighting the rapid antidepressant effects of ketamine revealed that this NMDA antagonist has downstream effects on brain derived neurotrophic factor (BDNF)[16]. BDNF is an important growth factor for neurons, and is implicated in neurogenesis and synaptic plasticity, specifically in long-term potentiation, which is critical for learning and memory. Depressed individuals show marked decreases of peripheral BDNF which is associated with a reduction in hippocampal size (an important brain structure involved in learning and memory); however, antidepressant medications, such as fluoxetine, have been shown to reverse this deficit, ultimately leading to a reduction in depressive symptoms[15]. However, typical antidepressants only work in a small fraction of individuals and in those that are responsive, effects of symptom reduction take several weeks to appear, which is much too long for many of those who suffer from this debilitating disorder[5].

In a randomized control study, researchers measured plasma BDNF levels in individuals with treatment resistant depression prior to being infused with ketamine as well as 240 minutes after being injected. Results indicated that BDNF levels significantly increased in patients intravenously infused with ketamine compared to controls. Furthermore, as an assessment of the association between ketamine, BDNF and depression, researchers measured levels of depression in individuals prior to receiving ketamine as well as at 240 minutes post-infusion using the Montgomery-Asberg Depression Rating Scale (MADRS). First, low BDNF levels in depressed individuals were associated with higher scores on the MADRS (indicating that low BDNF was associated with increases in depression). Furthermore plasma BDNF levels were shown to increase post-infusion and unsurprisingly this was reflected in decreased scores on the MADRS after treatment. The results from this study are significant in that they identify plasma BDNF as a relevant biomarker in treatment resistant depression and a significant target for ketamine in regards to it’s role as an antidepressant[16].

Closely related research looked at the association between BDNF, sleep slow wave (SWS) activity and ketamine[17]. One of the pathophysiological characteristics of most mood disorders, including depression, involves disturbances in normal sleep patterns. It has been proposed that one of the reasons why some depressed individuals sleep so much is to compensate for an overall decrease in SWS. Slow wave sleep is especially important for learning and memory, as it is a time when synaptic connections made during the day are strengthened[18]. Studies have shown that intra-hemispheric infusions of BDNF was associated with increased SWS activity; conversely infusions with a BDNF antagonist led to reductions in SWS. Furthermore, this decrease in SWS was shown to be related to declines in performance on a perceptual learning task, further evidencing the critical role of SWS in learning and memory[19]. With this knowledge in mind, researchers added another variable into the mix – ketamine. Following ketamine infusion, individuals showed a significant increase in both BDNF levels and SWS, as measured by electroencephalography (EEG) activity the first night post-infusion. Furthermore, most individuals showed a greater than 50% reduction in their score on the MADRS. Taken together, these results suggest ketamine’s integral role in producing rapid antidepressant effects through enhanced synaptic plasticity resulting from increases in BDNF and SWS[20].

4. Limitations and Future Directions

Although some doctors, especially in the United States are providing ketamine injections for their treatment resistant depressed patients, much more research is needed to fully understand the neurobiological mechanisms. One problem with the use of ketamine as an antidepressant is that it is extremely dangerous for depressed individuals with alcoholism and substance abuse issues to use a potentially addictive substance, thus making this an unsuitable treatment option for them[7]. Another significant caveat of using ketamine as an antidepressant it that it’s effect, although extremely rapid, is short-lived[12]. Most patients relapse into depression one week after receiving an infusion, suggesting that regular frequent infusions are required. However, this poses a series of problems. First, the long-term effects of constant ketamine use are not fully known. There are reports of increased kidney dysfunction, intense abdominal pain, psychosis, and even increases in depression, and potential for addiction in regular users of ketamine. In the near future it will be important to explore whether there are similar long-term effects of low-dose ketamine infusions as an antidepressant[7].
1. Vollenweirder, F. X. & Kometer, M. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nature Neurosci. 11, 642-651. (2010).
2. Carhart-Harris, R. L. et al. Implications for psychedelic-assisted psychotherapy: A functional magnetic resonance imaging study with psilocybin. Brit J Psychiat. 200, 238-244 (2012).
3. Downben, J. S. et al. Ketamine as an alternative treatment for treatment-resistant depression. Perspect Psychiat C. 49, 2-4. (2013).
4. Judd, L. et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Pscyhiatry. 57, 375-380. (2000).
5. Dupuy, J. M. et al. A critical review of pharmacotherapy for major depressive disorder. Int J Neruropsychopharmacol. 14, 1417-1431. (2011).
6. Mathew, S. J. et al. Ketamine for treatment-resistant unipolar depression. CNS Drugs. 26, 189-204. (2012).
7. Morgan, C. J. A. et al. Ketamine use: A review. Addiction. 107, 27-38. (2011).
8. Polito, V. et al. The experience of altered states of consciousness in shamanic ritual: The role of pre-existing beliefs and affective factors. Conscious Cogn. 19, 918-925. (2010).
9. Johnson, M. W. et al. Human hallucinogen research: Guidelines for safety. Psychopharm. 22, 603-620. (2008).
10. Duman, R. S. et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacol. 6, 35-41 (2012).
11. Zarate, C. A. et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 63, 856-864. (2006).
12. Young, S. N. Single treatments that have lasting effects: some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. J Psychiatry Neurosci. 38, 78-83. (2013).
13. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 329, 959-964. (2010).
14. Duman, R. S. & Aghajanian, G. Synaptic dysfunction in depression: potential therapeutic targets. Science. 338, 68-72. (2012).
15. Cornwell, B. et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 72, 555-561. (2012).
16. Haile, C. S. et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int J Neruropsychopharmacol. 17, 331-336. (2014).
17. Wallace, C. & Zarate, C. A. Ketamine, sleep, and depression: Current status and new questions. Curr Psychiatry Rep. 15, 394-401. (2013).
18. Thase, M. E. Depression and sleep: pathophysiology and treatment. Dialogues Clin Neurosci. 8, 217-226. (2006).
19. Faraguna, U. et al. A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. J Neurosci. 28, 4088-4095. (2008).
20. Duncan, W. C. et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int J Neruropsychopharmacol. 16, 301-311. (2013).
21. Niciu, M. J. et al. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annu Rev Pharmacol Toxicol. 54, 119-139. (2014).
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License