Ketamine has been used for over half a century as an anaesthetic, but interest has been steadily growing in its ability to rapidly decrease depressive symptoms. This interest has culminated in many studies attempting to elucidate its antidepressant mechanism, and in turn, these studies have contributed to our understanding of depressive disorders. Ketamine was first synthesised in 1962 as a dissociative anaesthetic, inducing a state of conscious sedation in which patients are awake, but cognitively dissociated from their pain (Young et al., 2011). In 1970, the Food and Drug Administration (FDA) approved ketamine as an anaesthetic, but throughout the 1970s ‘special K’, as it was known on the street, was gaining popularity as a recreational drug. The drug became notorious for its ability in high doses to lead users down a ‘K-hole’ – or a state of complete bodily dissociation (Muetzelfeldt et al., 2008). In 1999, the FDA scheduled the drug in the United Stated (US), banning non-medical use. While ketamine’s use and abuse was being argued over by policy makers, a team of scientists began to investigate ketamine as an antidepressant (Berman et al., 2000). Following this first human trial of ketamine as an antidepressant, the drug quickly garnered interest in the field of mental health, where since the publication of the fourth edition of the “Diagnostic and Statistical Manual of Mental Disorders” (DSM-IV) in 1994, depression was considered as a unitary concept and psychiatric disorder.
Depression and the pharmacological response
Major depressive disorder (MDD) is the most prevalent mental disorder, affecting roughly 16% of the world’s population at some point in their lives (Kessler et al., 2005). The dominant pharmacological hypothesis came about by trying to understand why certain monoaminergic-targeted medications seemed to alleviate depressive symptoms over time. The monoamine hypothesis of depression describes the disorder as the dysregulation of a group of monoaminergic neurotransmitters in the brain, specifically, the transport of dopamine, adrenaline, noradrenaline and serotonin into and out of synapses (Hirschfeld, 2000). First-line treatment of depression involves selective norepinephrine or serotonin reuptake inhibitors (SNRI/SSRI). These drugs inhibit the transport of key neurotransmitters out of the synapse between neurons. Unfortunately, less than half of those who suffer from MDD respond to monoamine-targeted medication, and for those who do, it takes at least two weeks and often longer for any symptom relief to become clinically noticeable (Kishimoto et al., 2016). Some studies have also linked SSRI treatment to an increased risk of suicide attempts and completed suicides (Fergusson et al., 2005; Healy, 2003). There is clearly a need for a more rapid and efficacious treatment of this debilitating disorder.
Ketamine as an antidepressant
Ketamine is rare in that it is a psychoactive substance that is classified in the U.S. in Schedule III under the Controlled Substances Act (Marshall, 1999) and available to be prescribed by physicians, making research accessible; however, the drug’s status as a non-patentable substance has proven to be a hurdle to funding research. Nevertheless, research into ketamine as an antidepressant has been ongoing since 2000 (Berman et al., 2000) and resulted in over 1500 studies. Studies have found that single intravenous infusions of ketamine at doses ranging from 0.1-0.5 mg/kg over 40 minutes show robust efficacy in short-term relief of MDD symptoms (Kishimoto et al., 2016). Symptoms decrease within 40-60 minutes and during the first 24 hours suicidality is also rapidly decreased. Interestingly, reduced suicidality was found to be a specific effect of ketamine, as it was also found in patients who did not respond to the antidepressant effects of the drug (Ryan et al., 2014). The promise for ketamine lies in its rapid-acting antidepressant and antisuicidal effects, as few current treatments achieve clinical significance in such a short time frame. Remission of depressive symptoms, on the other hand, only lasts between five and eight days, but can be extended to months through administration of repeated infusions (Murrough et al., 2013). This technique is somewhat controversial as the effects of repeated exposure to sub-anaesthetic doses of ketamine are yet to be known. Some patients who receive these sub-anaesthetic doses of ketamine report mild side-effects including headaches, dizziness and nausea, as well as dissociative effects and mild psychotomimetic experiences; however, these effects are transient and rarely outlast the time in which the drug is pharmacologically active (about 4 hours) (Coyle & Laws, 2015).
The glutamate theory of depression
Ketamine is a chemically promiscuous substance that interacts with many neurotransmitters in the brain, including the monoamines (Frohlich & Van Horn, 2015). Much of the research, however, has attributed ketamine’s antidepressant effects to its activation of the glutamate system. Glutamate is an excitatory neurotransmitter found in about 50% of synapses in the mammalian brain (all the monoamines together are found in only 15-20%) (Zarate & Niciu, 2015). It is the primary system by which neurons fire and communicate with one another and, as such, may be more pertinent to rapid changing of mood than monoaminergic systems.
The mechanism is complicated, but ketamine modulates glutamate by blocking, and thereby inhibiting, N-methyl-D-aspartate receptors (NMDAr) on interneurons. When active, these interneurons inhibit glutamatergic neurons in mood relevant brain areas; however, when blocked by ketamine, the disinhibition of these neurons leads to an increase in glutamatergic synaptic transmission in brain areas responsible for mood. Ultimately, the increase in glutamate activates a cascade of effects that results in neuroplasticity or neural regeneration – morphological changes to neurons in these brain areas (Kavalali & Monteggia, 2012). According to this hypothesis, the drug begins by causing chemical changes which result in non-chemical, morphological changes. It is these physical changes in the brain that could explain the persisting antidepressant effects of the drug once its pharmacological activity has ended. While NMDAr are believed to mediate these beneficial effects, recent research comparing ketamine with selective NMDAr antagonists shows that the selective NMDAr antagonists are not nearly as effective as ketamine in treating depression (Kishimoto et al., 2016; Sanacora & Schatzburg, 2015; Zanos et al., 2016). This suggests the possibility of an alternate mechanism of action.
Competing mechanisms
Excitement about ketamine as a wonder drug for depression should be tempered by a number of safety concerns about the medication. Firstly, it can induce psychedelic experiences which could be dangerous for those with a family history of psychotic disorders. Many pharmacologists, physicians and chemists have been searching for ways of achieving anti-depressant effects separate from the psychedelic experiences by adjusting doses to sub-anaesthetic levels, or exploring metabolites and stereoisomers of ketamine. Other more psychotherapeutically oriented researchers claim that the psychedelic and dissociative effects of the drug are part and parcel of its success in treating depression when combined with therapy, and that stripping the drug treatment of these mind-altering effects is akin to practicing homeopathy (Wolfson, 2014).
One such psychiatrist, Terrence Early (2014), suggests that ketamine works via the mechanism of ‘action-facilitated emotional learning.’ According to Early, patients on ketamine dissociate from their bodies, and are thus able to remember negatively charged emotional memories or trauma without the anxiety that would normally accompany these memories. Ketamine attenuates the anxiety response when trauma is revisited in therapy, and this in turn allows these memories to gradually become manageable. The age-old debate between minimising the psychedelic effects of psychedelics and embracing them for their therapeutic potential is a complex one that is present throughout the literature of psychedelic science, and involves political narratives of the war on drugs and freedom of thought.
Broadening the scope of treatment
Looking ahead to the broadened use of ketamine outside of hospital settings, addiction liability is an issue that worries some researchers (Sanacora & Schatzburg, 2015; Zhang et al., 2016), especially considering that nearly one-third of people who suffer from depression also meet criteria for substance use disorders (Davis et al., 2008). To date, trials involving ketamine almost always exclude a comorbid substance abuse disorder and this means we have very little data regarding ketamine’s addiction potential for this significant population of depressed patients. Ketamine addiction is well documented, but only at doses above 1 mg/kg (Newport et al., 2015). Current trials treating depression typically use doses of 0.5 mg/kg and never over 1.0 mg/kg. Nevertheless, the medical field has an embarrassing history of creating addictions through prescription medications like laudanum, heroin and cocaine, and we don’t have to look very far to see the current epidemic of prescription opiate addiction. Because of the drug’s short half-life, in order to achieve remission of longer than one week, repeated doses of ketamine are required, potentially increasing the likelihood of tolerance and addiction to the medication. Currently there is a paucity of research on the adverse effects of long-term repeated ketamine usage.
Ketamine is currently approved by the FDA via intravenous (IV) or intramuscular (IM) routes for large-dose anaesthesiology. This requires the presence of an anaesthesiologist and must take place in a hospital setting. This expensive, invasive and highly medicalised treatment model shows little regard for set and setting, which plays such an important role in ensuring meaningful psychedelic experiences. It has been shown that patients who received ketamine in electroconvulsive therapy rooms have worse outcomes than patients who received the medication in comfortable, relaxed settings (Ryan et al., 2014).
Alternate routes of ketamine administration have been developed and are currently being researched, including intranasal, subcutaneous, oral and sublingual (Lara et al., 2013; Mathews et al., 2012; Opler et al., 2016); however, bioavailability of ketamine is less than 50% for oral, subcutaneous and intranasal routes of administration compared to 93% for the more invasive routes (Clements et al., 1982). The antidepressant response to these alternate routes is also lower than IV or IM administration (Ryan et al., 2014). Sub-anaesthetic doses, not requiring the presence of anaesthesiologists and which can be administered in more comfortable settings, have shown antidepressant efficacy (Berman et al., 2000; Zarate et al., 2006). If off-label prescriptions are being written and administered, informed consent and integration in a therapeutic treatment are important set and setting factors for maximising the effect of the medication.
On the horizon
An exciting new article was published in Nature in May 2016, which claims to have found the key metabolite of ketamine responsible for the sustained antidepressant effects. The compound of interest was tested using animal models and found to be non-addictive and non-psychotomimetic (Zanos et al., 2016). Ketamine as it is generally administered is a racemic mixture of S-ketamine and R-ketamine (both left- and right-handed molecules in more or less equal parts). The body converts both of these enantiomers into a number of metabolites. S-ketamine and its metabolites are known to have three to four times greater affinity for NMDAr than R-forms, leading researchers to believe that S-ketamine could be used in smaller doses to achieve similarly potent effects; however, Zanos and colleagues identified (2R, 6R)-hydroxynorketamine (R-HNK) – a metabolite of ketamine with two right-handed chiral centres – as essential to the potent antidepressant effect.
Unexpectedly, R-HNK does not bind to or inhibit NMDAr, calling into question the NMDAr hypothesis of ketamine. While the target of R-HNK is not yet known, it was shown that R-HNK increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr)-mediated postsynaptic potentials in the hippocampus, even after the drug’s pharmacological activity has ended. It is the upregulation of these excitatory glutamatergic AMPAr that is hypothesised to be responsible for the longer-lasting antidepressant effects of ketamine. This novel NMDAr-independent, non-addictive and non-psychotomimetic antidepressant mechanism is an exciting find (Zanos et al., 2016), but this research needs to be replicated and scaled up to human trials before any firm conclusions can be drawn as to its efficacy in treating depressive disorders.
Ketamine has emerged as a first-in-class rapid-acting antidepressant medication with a unique mechanism of action that differentiates it from the current psychiatric tools for depression. We may be on the brink of next-generation rapid-acting antidepressant medication; however, excitement about ketamine’s antidepressant benefits should be tempered by issues of safety, including adverse psychotomimetic effects, abuse potential, and costly invasive routes of administration. Before the FDA approves ketamine as a medication for MDD in broader clinical contexts, research into adverse effects of prolonged use needs to be done along with the standardisation of optimal dosing, route of administration and frequency of ketamine administration. Even in the early days of research, and with these safety concerns in mind, ketamine’s ability to rapidly decrease depressive and suicidal symptoms allows physicians to ethically treat the most severe cases of depression in emergency room contexts. At the very least, it can give clinicians time to implement alternative therapies and allow for the slower-onset, first-line treatments to reach efficacy.
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