Ketamine for treatment-resistant depression: recent developments and clinical applications: Table 1

Abstract

Approximately one-third of patients with major depressive disorder (MDD) do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. There is a clear unmet need for rapidly acting and more efficacious treatments. We will review recent developments in the study of ketamine, an old anaesthetic agent which has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD, focusing on clinically important aspects such as dose, route of administration and duration of effect. Additional evidence suggests ketamine may be efficacious in patients with bipolar depression, post-traumatic stress disorder and acute suicidal ideation. We then discuss the safety of ketamine, in which most neuropsychiatric, neurocognitive and cardiovascular disturbances are short lasting; however, the long-term effects of ketamine are still unclear. We finally conclude with important information about ketamine for primary and secondary physicians as evidence continues to emerge for its potential use in clinical settings, underscoring the need for further investigation of its effects. INTRODUCTIONUnipolar major depressive disorder (MDD) affects approximately 350 million people, making it the leading cause of disability worldwide, associated with harmful consequences onto the well-being of affected individuals and society. 1 2 Currently prescribed antidepressant treatments targeting the monoamine system only alleviate depressive symptoms in about half of the patients.3 These rates become significantly lower in patients who had already failed to improve after two or more antidepressant treatments at adequate doses and duration (ie, treatment-resistant depression, TRD). 4 This results in unnecessary exposure to lengthy trials of ineffective medications. Moreover, currently approved antidepressants targeting the monoamine system have a long onset in initiating response, typically 6-12 weeks. There is a clear unmet need for more efficacious and rapidly acting antidepressants. Emerging evidence of the impaired relationship between the glutamate neurotransmitter system and neuronal plasticity in depression 5 has guided the search for alternative antidepressant treatments. Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate receptor antagonist, on the WHO Essential Medicine List for use as an anaesthetic and prescribed off-label to treat chronic pain.6 7 Research since 2006 on the use of ketamine for treating depression has shown that subanaesthetic doses (0.5 mg/kg) administered over a 40 min intravenous (IV) infusion period can have rapid-acting antidepressant effects on patients with TRD.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

“…Accordingly, the sustained antidepressant response cannot be attributed to the direct receptor effects of ketamine, but instead may be mediated by activation of crucial down stream signalling cascades. 2,12,15 Not surprisingly, ketamine's unprecedented rapid and sustained antidepressant effects as well as its high response rates, especially in TRD populations, have inspired massive efforts to uncover the molecular mech anisms mediating the drug's unique therapeutic profile.…”

“…2,9 In addition, ketamine, or "Special K," is used as a recreational drug and thus has the potential to be abused, and prolonged use may cause neurotoxic effects. 1,3 Hopefully, the identification of the mechanism of action underlying ketamine's anti depressant effects will assist in the development of novel rapid acting antidepressants that lack the features noted above that currently limit ketamine's wider clinical use.…”

“…51 In addition, BDNF is associated with antidepressant responses to classical antidepressants (e.g., SSRIs, TCAs), which lack efficacy in BDNF knockout mice. 2,5,57 Although it takes several weeks for these agents to trigger BDNFmediated synaptic plasticity, such changes can occur within hours following ketamine administration. 2,5 Another key downstream convergence pathway impli cated in depression susceptibility and ketamine action is the mTOR signalling pathway, which regulates activity dependent synaptic plasticity and translation of synaptic pro teins.…”

“…2,5,57 Although it takes several weeks for these agents to trigger BDNFmediated synaptic plasticity, such changes can occur within hours following ketamine administration. 2,5 Another key downstream convergence pathway impli cated in depression susceptibility and ketamine action is the mTOR signalling pathway, which regulates activity dependent synaptic plasticity and translation of synaptic pro teins. 41,59 In addition, mTOR activation is accompanied by in hibition of eukaryotic elongation factor 2 (eEF2) kinase, desuppression of eEF2 and increased synaptic protein syn thesis (e.g., BDNF, GluA1-2, PSD95); promotes synapse for mation and maturation; and is believed to underlie the syn aptogenic effects of ketamine.…”

What Is New about New Antidepressants?

“…However, as noted earlier, ketamine has a number of other actions, including antagonism of nicotinic and muscarinic cholinergic receptors [23], inhibition of GSK3β [24], increased release of norepinephrine and dopamine in the bed nucleus of the stria terminalis [44], and binding to μ-opioid receptors [30], among others. In subanesthetic doses, intravenous ketamine has been found to be rapidly effective for symptoms of treatment-resistant unipolar and possibly bipolar depression, and acute suicidal ideation [45-47], with other applications having a much smaller evidence base [48]. A single intravenous dose of ketamine as monotherapy for MDD produces a rapid antidepressant effect that peaks within 24 h, with an overall OR of 7.55 in controlled studies [49].…”