Department of Psychiatry AG Stimulationsverfahren in der Psychiatrie. The Role of Ketamine in Treatment-Resistant Depression
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1 Department of Psychiatry AG Stimulationsverfahren in der Psychiatrie The Role of Ketamine in Treatment-Resistant Depression
2 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 2 Presentation Overview 1. Background information - The treatment-resistant depression - Ketamine 2. Usage of Ketamine in depressive disorders The latest studies 3. Outlook and conclusion
3 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 3 The Major Depression - Lifetime prevalence ca. 18%. - 55%-65% experience more than one depressive episode. - Its the mental disorder with the highest risk for suicide.
4 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 4
5 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 5 The treatment-resistant depression - Effects of antidepressants occure after weeks, sometimes months. - Ca 60 % of the patients do not respond to the first antidepressant after 8 weeks. - Ca. 30% of do not respond to the second antidepressant as well. - Ca 15 % remain depressive even after several antidepressants.
6 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 6 What is Ketamine? - Ketamine acts as a selective uncompetitive antagonist of the NMDA receptor, an ionotropic glutamate receptor. - The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine.
7 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 7 What is Ketamine?
8 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 8 What is Ketamine? Antagonism of the NMDA receptor is thought to be responsible for: + Anesthetic and amnesic effect -> + Dissociative and hallucinogenic effect -> + Antidepressive effect ->
9 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 9 Use of Ketamine against Depression - 3 treatments per week, over 2 weeks. - Ketamin 0,5mg/kg (sub-anaesthetic). - Maintenance therapy unclear. E.g. 1x/month.
10 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 10 The latest studies
11 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 11 Ketamine vs. Active Placebo (Midazolam) Murrough et al. Am J Psychiatry 2013 Relapse-rate >50% after the first week.
12 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 12 Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression Murrough et al. Biol. Psychiatry 2013 The ov - The overall response rate at study end was 70.8% (!) - Response at study end was strongly predicted by response at four hours - Among responders, median time to relapse following the last ketamine infusion was 18 days.
13 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 13 Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Daly et al. Jama Psychiatry 2018 N = 126 Up to 50% response Rate (depending on dose)
14 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 14 NMDA-Dependent-Burst-Hypothesis Yang et al. Nature The lateral habenula ( anti-reward center ) neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals. - Burst-evoking photostimulation of the lateral habenula drives behavioural despair and anhedonia. - Blockade of NMDAR-dependent bursting activity in the lateral habenula, mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression.
15 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 15 Non-NMDA-Antagonist-Hypothesis - A prominent hypothesis for the mechanism of action of ketamine is that it acts via direct inhibition of NMDARs localized to interneurons. - However, the results of human treatment trials indicate that alternative NMDAR antagonists lack the robust, rapid and/or sustained antidepressant properties of ketamine.
16 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 16 Non-NMDA-Antagonist-Hypothesis Zanos et al., Nature The (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. - These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). - (2R,6R)-HNK lacks ketamine-related side effects. - This might have and have relevance for the development of next-generation, rapid-acting antidepressants.
17 Dr. Heiko Albrecht The Role of Ketamine in Treatment-Resistant Depression 17 Outlook and conclusion Ketamine has a quick an solid antidepressive effect. The exact mechanism of this effect has to be discovered. FDA approval could take place in the next years (fast-track status). Maintenance therapy and the implemention of other (psychological) treatments should be elaborated. Studies about the long-term effects and side-effects are lacking.
18 Department of Psychiatry AG Stimulationsverfahren in der Psychiatrie Большое спасибо! / Vielen Dank! Martinistraße 52 D Hamburg Ansprechpartner Dr. H. Albrecht h.albrecht@uke.de
HHS Public Access Author manuscript Mol Psychiatry. Author manuscript; available in PMC 2018 June 13.
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