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Oral ketamine for the treatment of pain and treatment-resistant depression

  • Robert A. Schoevers (a1), Tharcila V. Chaves (a1), Sonya M. Balukova (a1), Marije aan Het Rot (a2) and Rudie Kortekaas (a3)...
Abstract
Background

Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.

Aims

To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain.

Method

Searches in PubMed with the terms ‘oral ketamine’, ‘depression’, ‘chronic pain’, ‘neuropathic pain’, ‘intravenous ketamine’, ‘intranasal ketamine’ and ‘subcutaneous ketamine’ yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.

Results

Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects.

Conclusions

Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.

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Copyright
Corresponding author
Robert A. Schoevers University Medical Center Groningen, Department of Psychiatry, Hanzeplein 1, P.O. Box 30001(CC-11), 9700 RB Groningen, The Netherlands. Email: r.a.schoevers@umcg.nl
Footnotes
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See editorial, pp. 101–103, this issue.

Declaration of interest

None.

Footnotes
References
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Oral ketamine for the treatment of pain and treatment-resistant depression

  • Robert A. Schoevers (a1), Tharcila V. Chaves (a1), Sonya M. Balukova (a1), Marije aan Het Rot (a2) and Rudie Kortekaas (a3)...
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eLetters

How much ethanol is in ketamine`s antidepressant response?

Udo Bonnet, Psychiatrist, MD, Professor, Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Germany
17 May 2016

With great interest I read the informative review of Schoevers et al1 about ketamine`s potency in the management of pain and treatment-resistant depression. The authors perceive a latent risk of ketamine misuse resulting from these treatments and forecast misuse becomes more prominent when ketamine will be used broadly in clinical practice.1 At this juncture, it should be emphasized that acute ethanol shares some pharmacological features with ketamine, all being parts of a cascade that precipitates enhanced synaptogenesis and connectivity in cortico-limbic networks:2 i) non-competitive antagonism of glutamatergic NMDA-receptors, ii) disinhibition of pyramidal cells producing an extracellular glutamate surge iii) amplification of glutamate non-NMDA receptor- and downstream mTOR-signaling pathways, iv) increase of neurotrophins (BDNF, NGF) [all referenced elsewhere].3 All of which are assumed to contribute to the generation of ketamine`s rapid but short-term antidepressant response (AR):2

When ethanol vapor is repeatedly applied to rodents, their prefrontal pyramidal neurons develop an increase in dendritic spine density in the first abstinence days,4 which may resemble the synaptic remodeling observed after a single sub-anesthetic ketamine pulse.2 While the first is interpreted to reflect plasticity changes on the way to addiction,4 is the second shown to reverse chronic-stress-mediated decreases in spine density and assumed to represent morphologically the AR.2 Do a few ethanol pulses work similarly `refreshing´ on stressed spines of a non-addicted brain? Intriguingly, low ethanol doses are followed by antidepressant-like effects in Porsolt`s swim test on mice.3 Against this background, there remain in my mind a few primarily depressed alcohol dependents, who reported an improvement of their depressed state after a few glasses of beer or wine, which lasted for some abstinent days (ethanol`s AR?), however, only in the beginning of their drinking career. To cope with depression more sustainably, these patients gradually increased the frequency and amount of alcohol intake, which resulted in hangover and tolerance to ethanol`s putative AR. Ethanol`s AR might have been weaker than that of ketamine considering ethanol´s weaker antagonism of NMDA-receptors and stronger stimulation of GABA-A-receptors.3 Once addicted, aversive withdrawal symptoms, craving and alcohol seeking behavior occurred in these patients, which worsened their depression and fueled more frequent or continuous drinking.

Abstaining alcohol dependents have lower limbic brain glutamate concentrations than normal controls,5 suggesting a long-term adaptation to too many glutamate surges alongside harmful drinking. Can this also happen to the brain when ketamine is frequently applied, thus giving birth to an aberrant learning process, such as addiction? Moreover, prolonged intake of either ethanol or ketamine is associated with gene expression of specific NMDA-receptor subunits, sustained inhibition of synaptic long-term potentiation and decreasing levels of neurotrophins,3 themselves all related to an addicted brain and precursors to neurotoxicity.

Ketamine and ethanol are good examples for psychoactive drugs, whose wanted, even therapeutic effects (e.g. AR) can silently turn to adverse effects (e.g. addiction, neurotoxicity) after exceeding an individual critical amount and duration of intake. This is based on their ability to use the same pathway to trigger cortico-limbic plasticity being involved in the generation of AR, tolerance and addiction. If at all possible, finding the optimal route of administration and dosing of ketamine to produce a preferably long-term AR without burgeoning tolerance (even to ketamine`s AR) remains a big challenge.3

References

1Schooners RA, Chaves TV, Belousova SM, Rot MA, Koreas R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry 2016; 208(2): 108-13.

2Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett 2015; 601: 20-9.

3.Bonnet U. Long-Term Ketamine Self-Injections in Major Depressive Disorder: Focus on Tolerance in Ketamine's Antidepressant Response and the Development of Ketamine Addiction. J Psychoactive Drugs 2015; 47(4): 276-85.

4.Kim A; Zamora-Martinez ER; Edwards S, Mandyam CD. Structural reorganization of pyramidal neurons in the medial prefrontal cortex of alcohol dependent rats is associated with altered glial plasticity. Brain Struct Funct 2015; 220 (3): 1705-20.

5.Thoma R, Mullins P, Ruhl D, Monnig M, Yeo RA, Caprihan A, Bogenschutz M, Lysne P, Tonigan S, Kalyanam R, Gasparovic C. Perturbation of the glutamate-glutamine system in alcohol dependence and remission. Neuropsychopharmacology 2011; 36(7): 1359-65.

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