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Ketamine Infusions

The Science

OVERVIEW

In recent years, overwhelming evidence has substantiated the potential benefits of ketamine in treating psychiatric disorders, particularly depression and chronic pain. Extensive research has indicated that ketamine can provide rapid and significant improvements of depressive symptoms, even for patients with treatment resistant depression (1, 2). Additionally, clinical data suggests that ketamine treatment can effectively treat many types of chronic pain, including treatment of complex regional pain syndrome (CRPS) (3, 4, 5). In order to discuss the clinical applications of ketamine in treating psychiatric disorders like depression and chronic pain, it is necessary to consider what is known about the molecular and cellular basis of ketamine action.

THE GLUTAMATERGIC SYSTEM

Ketamine is a drug classified as a dissociative anesthetic hallucinogen because it exerts its biochemical actions on the glutamatergic system. The glutamatergic system refers to the neurons that use glutamate as a neurotransmitter (signaling molecule). As glutamate is the major excitatory neurotransmitter in the mammalian brain, it is responsible for transmitting activating signals to glutaminergic neurons. Tight regulation of extracellular (outside of cells) glutamate levels is of utmost physiological importance because glutamate is both found in extremely high concentrations and because its excitatory effects are very potent (6). Glutamate functions as a neurotransmitter by acting at two classes of receptors, ionotropic glutamate receptors and metabotropic glutamate receptors. When glutamate binds to ionotropic receptors, the receptors change shape and allow for cations (positively charged molecules) to move from one side of the neuronal membrane to the other. Metabotropic receptors respond to glutamate by activating signaling proteins that promote downstream cellular events. The ionotropic glutamate receptors are called N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and kainate (KA), but for the purposes of this paper the most important ionotropic glutamate receptor is NMDA (6) 

In the absence of neuronal firing, the flow of ions through NMDA receptors (NMDAR) channels is blocked by a magnesium ion. In order for NMDAR activation to occur, two steps are necessary. The membrane depolarization (a change in the electrical voltage of a neuronal membrane) is required to remove the magnesium ion from the ion channel, and the binding of glutamate to the NMDAR is required to permit sodium and calcium ions to flow into the neuron and potassium ions to flow out of the neuron (7). In healthy individuals, glutamate signaling through NMDARs is responsible for neuroplasticity (the ability of the brain to learn, adapt and change in response to new conditions) (7). Neuroplasticity is achieved through two opposing mechanisms at the NMDA receptor, long-term potentiation (LTP) and long-term depression (LTD). LTP strengthens specific synapses and LTD weakens specific synapses (7). Due to the high potency and high concentration of glutamate in the brain, glutamate regulation is essential for appropriate NMDA receptor responses (7). 

GLUTAMATE IN DEPRESSION

NMDAR dysfunction is associated with depression (7, 8, 9). The exact mechanisms by which depression occurs still remain unclear, but evidence has suggested that excessive glutamate signaling at NMDA receptors may be in part responsible (8, 9). This theory has been extensively studied since 1990 because conventional antidepressant therapies, often referred to as monoamine reuptake inhibitors, have long therapeutic delays, often taking months to see any effects, and unfortunately do not provide symptomatic relief for almost a third of depressed patients (10). These medications were designed to keep serotonin, norepinephrine and dopamine (other neurotransmitters) in higher concentrations at signaling junctions to promote their actions (7). Monoamine reuptake inhibitors fail to address the theory that depression may be caused by excessive glutamate signaling at NMDA receptors. Fortunately, extensive research into the role of glutamate signaling at NMDAR in depression patients has revealed that a single ketamine intravenous infusion can produce a significantly rapid and sustained antidepressant response (11, 12). 

ANTIDEPRESSANT MECHANISMS OF KETAMINE

The mechanism by which ketamine improves symptoms of depression is not completely understood, but, in addition to affecting NMDAR signaling, ketamine may involve another class of glutamate receptors, AMPA. Normal functioning of AMPARs are thought to be essential for modifying synaptic strength and supporting cellular remodeling in response to learning (13). AMPA receptors and NMDA receptors are antagonists, meaning the actions they elicit oppose one another (14). AMPA receptor actions may serve as a feedback mechanism in which the activation of AMPAR may lead to the inhibition of glutamate release and glutamate activity (14, 15). Recently, researchers discovered that the antidepressant properties of ketamine modulate glutamate activity in the brain in two ways: by blocking NMDA receptors and by mediating activation of AMPA receptors (14). Ketamine blocks NMDA ion channels, causing the glutamate bound to the NMDAR to release into the extracellular space, effectively “freeing” this glutamate to act at AMPA receptor sites (7, 14). The binding of glutamate to AMPAR may then induce the inhibition of glutamate recycling and release (14). 

In addition to exerting antidepressant effects by activating AMPA and reducing glutamate signaling, ketamine may also modulate the production of neurotrophic factors, molecules that are essential for neural plasticity (15). The expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor, has been demonstrated to be significantly reduced in patients with depression and several meta-analyses have revealed that blood BDNF levels are also significantly reduced in patients with depression (15, 16, 17). Further, animal models of stress have revealed that depression-like behavior is associated with reduced BDNF expression in certain murine brain areas (15). BDNF is synthesized in response to activation of a signaling pathway called mTOR. Ketamine-mediated stimulation of AMPA receptors can lead to the downstream activation of mTOR, leading to a rapid production of BDNF. Evidence now supports that BDNF is required for and may partly mediate the significant and rapid antidepressant effects of ketamine (18, 19, 20). Additionally, studies have shown that ketamine treatment both significantly increased BDNF protein levels and significantly increased synaptic plasticity in mice (21). Although the mechanism by which ketamine-mediated enhanced synaptic plasticity and increased BDNF protein expression are related in humans remains unclear, a recent study demonstrated that ketamine infusions significantly increase synaptic plasticity in humans (22).

As a powerful regulator of glutamate, ketamine has many clinical applications for expanding treatment options for mental health disorders like depression. In particular, the incredibly rapid onset of antidepressant effects that ketamine infusions produce is of utmost clinical importance to patients with depression suffering from suicidal ideation. A recent systematic review and meta-analysis concluded that single-dose intravenous ketamine infusions remarkably reduce patients’ suicidal thoughts as soon as 2 hours after infusion (23). These results highlight ketamine as a fast-acting and successful therapeutic avenue for individuals struggling with severe depression. In addition, around 40% of patients with treatment-resistant depression (TRD) present with cognitive deficits. The results from another recent systematic review suggest that TRD patients treated with ketamine infusions showed improved complex and simple working memory, improved processing speed and improved verbal learning memory (24). These results provide further evidence for the safety and efficacy of using therapeutic ketamine in treatment plans for patients with depression.


CITATIONS
  1. Mandal, Suprio et al. “Efficacy of ketamine therapy in the treatment of depression.” Indian journal of psychiatry vol. 61,5 (2019): 480-485. 
  2. Marcantoni, Walter S et al. “A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019.” Journal of affective disorders vol. 277 (2020): 831-841. doi:10.1016/j.jad.2020.09.007
  3. Orhurhu, Vwaire et al. “Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials.” Anesthesia and analgesia vol. 129,1 (2019): 241-254. doi:10.1213/ANE.0000000000004185
  4. Taylor, Samantha-Su et al. “Complex Regional Pain Syndrome: A Comprehensive Review.” Pain and therapy, 10.1007/s40122-021-00279-4. 24 Jun. 2021, doi:10.1007/s40122-021-00279-4
  5. Zhao, Jianli et al. “The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis.” Current pain and headache reports vol. 22,2 12. 5 Feb. 2018, doi:10.1007/s11916-018-0664-x
  6. ​​Niciu, Mark J et al. “Overview of glutamatergic neurotransmission in the nervous system.” Pharmacology, biochemistry, and behavior vol. 100,4 (2012): 656-64. doi:10.1016/j.pbb.2011.08.008
  7. Adell, Albert. “Brain NMDA Receptors in Schizophrenia and Depression.” Biomolecules vol. 10,6 947. 23 Jun. 2020, doi:10.3390/biom10060947
  8. Abdallah, Chadi G et al. “The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 43,10 (2018): 2154-2160. doi:10.1038/s41386-018-0136-3
  9. Marsden, W N. “Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression.” Medical hypotheses vol. 77,4 (2011): 508-28. doi:10.1016/j.mehy.2011.06.021
  10. Gaynes, Bradley N et al. “Defining treatment-resistant depression.” Depression and anxiety vol. 37,2 (2020): 134-145. doi:10.1002/da.22968
  11. Phillips, Jennifer L et al. “Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.” The American journal of psychiatry vol. 176,5 (2019): 401-409. doi:10.1176/appi.ajp.2018.18070834
  12. Singh, Jaskaran B et al. “A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression.” The American journal of psychiatry vol. 173,8 (2016): 816-26. doi:10.1176/appi.ajp.2016.16010037
  13. Chater, Thomas E, and Yukiko Goda. “The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity.” Frontiers in cellular neuroscience vol. 8 401. 27 Nov. 2014, doi:10.3389/fncel.2014.00401
  14. Lazarevic, V., Yang, Y., Flais, I. et al. “Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors.” Mol Psychiatry. (2021): https://doi.org/10.1038/s41380-021-01246-3
  15. Sen, Srijan et al. “Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications.” Biological psychiatry vol. 64,6 (2008): 527-32. doi:10.1016/j.biopsych.2008.05.005
  16. Guilloux, JP., Douillard-Guilloux, G., Kota, R. et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry 17, 1130–1142 (2012). https://doi.org/10.1038/mp.2011.113
  17. Tripp, Adam et al. “Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.” The American journal of psychiatry vol. 169,11 (2012): 1194-202. doi:10.1176/appi.ajp.2012.12020248
  18. Marchi, Mario et al. “Effects of adenosine A1 and A2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes.” British journal of pharmacology vol. 136,3 (2002): 434-40. doi:10.1038/sj.bjp.0704712
  19. Yang, Tao et al. “The Role of BDNF on Neural Plasticity in Depression.” Frontiers in cellular neuroscience vol. 14 82. 15 Apr. 2020, doi:10.3389/fncel.2020.00082
  20. Fukumoto, Kenichi et al. “Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.” Proceedings of the National Academy of Sciences of the United States of America vol. 116,1 (2019): 297-302. doi:10.1073/pnas.1814709116
  21. Autry, Anita E et al. “NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.” Nature vol. 475,7354 91-5. 15 Jun. 2011, doi:10.1038/nature10130
  22. Höflich, A., Kraus, C., Pfeiffer, R.M. et al. Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial. Transl Psychiatry 11, 200 (2021). https://doi.org/10.1038/s41398-021-01318-6
  23. Xiong, Jiaqi et al. “The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis.” Journal of psychiatric research vol. 134 (2021): 57-68. doi:10.1016/j.jpsychires.2020.12.038
  24. Gill, Hartej et al. “The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research.” Neuroscience and biobehavioral reviews vol. 120 (2021): 78-85. doi:10.1016/j.neubiorev.2020.11.020

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