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Ketamine and Psychedelics: Next-Wave Antidepressants

Posted by on January 21, 2021 in depression, Mental Illness, Neuroscience, Pharmacology | 1 Comment

Ketamine and psychedelics are making headlines as new alternative antidepressant therapeutics. For years scientists have been studying the benefits of these drugs on the brain and exciting new research has led to the idea that our understanding of what underlies depression could be wrong and these next-wave antidepressants could be another remedy of one of the most common psychiatric diseases[1]. What do these drugs have in common and how do they challenge our understanding of depression?

What’s really behind depression?

Depression is the leading cause of disability worldwide[1], yet the mechanisms underlying it still remain elusive. We know that depression affects 3 main areas of the brain: the prefrontal cortex (which controls our complex behavior and decision making), the hippocampus (the brain area involved in memory formation), and the amygdala (the area responsible for aggression, fear, and other emotions). In brains afflicted with depression, there is more degeneration of cells responsible for information processing- gray matter- and the worse the depression severity, the worse this atrophy is[1]. Patients with depression also have structural changes in the brain cells that make up these areas. Specifically, on small protrusions of the neuron called dendritic spines. These spines make connections as well as store/process information for the cell. In patients with depression, there are less spines and an inability to grow new ones. The malfunction of these little spines could have major effects on things like learning and memory and the overall ability of synapses to grow and reform- referred to as the plasticity of synapses[2]. Being able to regulate the number, size, and shape of the spines is important for a normal stress response, thus plasticity plays a big role in being able to face a new challenge and have an appropriate behavior response.

Figure of a type of brain cell called a neuron showing the dendritic spines and how they form synapses

Normally, this necessary plasticity in the brain is regulated by a protein called brain-derived neurotrophic factor (BDNF). This protein is super important for learning and memory and its reduction is associated with depressed subjects[3]. Increasing the levels of this protein BDNF allows test subjects to perform better in stressful tasks. This has led scientists to construct a new hypothesis of how depression might be acting: the neurotrophic hypothesis. The neurotrophic hypothesis is the belief that changes in plasticity that no longer allow proper function is the underlying cause for depression. Thus proper antidepressants are those that would really treat the causes by promoting BDNF secretion, ultimately leading to new spines and new synapses. 

Classical antidepressants may not be the best we can do

This new model of depression is a bit different than the traditional view which has informed our development of antidepressant drugs. The older paradigm is that depression is caused by imbalances of chemicals in the brain like serotonin and dopamine, which modulate mood and motivation. Antidepressants like selective serotonin reuptake inhibitors (SSRIs) like Prozac, selective norepinephrine reuptake inhibitors (SNRIs), and tricyclics seek to rectify these imbalances. While classical antidepressants have been shown to also increase BDNF levels[4], they have a very slow onset time of several weeks to several months. Furthermore, they have limited efficacy, with 30-40% of patients never experiencing improvement and thus being labeled as “treatment resistant”1. This all has presented scientists with a clear need for rapid and effective antidepressants.  

Ketamine and its effects 

Ketamine, traditionally an anaesthetic, has been revolutionizing antidepressants. It has been shown in low doses to have rapid effects for patients with depression since its recent approval for  clinical use. Patients administered these low doses by doctors can have antidepressant effects within 4 hours[1], which is much faster than the weeks to months expected with traditional antidepressants. Not only is ketamine fast, it is also broadly effective. Among treatment resistant individuals, it is 70% effective[5].

Figure of the effects of low doses of ketamine on a neuron after a control dose (VEH) and a ketamine dose (KEH) and how the density of spines and synapses increase from [12]

How is ketamine so effective? The mechanisms underlying ketamine’s success as an antidepressant point to its ability to promote plasticity in the prefrontal cortex and the hippocampus. On the molecular level, ketamine blocks specific neuronal receptors called NMDA receptors, which activate other receptors called AMPA receptors. As this cascades down the cell signaling sequence, eventually our star protein BDNF is upregulated through a notable pathway known as mTOR. What is notable here is that ketamine is able to affect BDNF levels and the mTOR pathway is known to drive structural plasticity necessary for remedying the symptoms of depression[5]. 

Flow diagram of how low doses of ketamine has its effects on neurons

While ketamine is rapid and effective, its effects are very temporary, with patients needing to return for another dose within 1-2 weeks[5]. Furthermore, ketamine use remains restrictive as it has high potential for abuse and toxicity. In fact its toxic effects have been used in the past  to model schizophrenia in animals[6]. For these reasons, doctors must administer ketamine and since the effects wear off relatively quickly, researchers have been looking for other drugs that have the same benefits as ketamine, while also being safer for patients and lasting longer. 

Psychedelics as a potential treatment

While not currently approved as a clinical treatment, psychedelics have been shown to have promising results in the field of antidepressants. Psychedelics activate the serotonin receptors, receptors long implicated in depression and mood disorders. Post-mortem samples of depressed and suicidal patients show increased serotonin receptors[7,8] and treatment with antidepressants has been associated with a reduction in serotonin receptor density[9]. The very receptors that are thought to produce psychedelics’ hallucinogenic effects are the same ones thought to give them antidepressant qualities. Curiously, though ketamine activates AMPA receptors, both psychedelics and ketamine seem to converge and use the same signaling pathway, the mTOR cell signaling pathway, that elevates levels of BDNF and promotes neural plasticity in the circuitry that is implicated in the pathophysiology of mood disorders[10].

Another way that psychedelics may also improve symptoms of depression is through reducing inflammation. It is now recognized that inflammation plays a significant role in the pathophysiology underlying many psychiatric disorders and depression. Serotonin receptor activation in immune cells can result in lower levels of proinflammatory cytokines[9]. Additionally,  high levels of those cytokines have been associated with depression, thus reducing inflammation in the brain may produce antidepressant effects[11]. This could also be another reason why psychedelics could be a better choice than ketamine for use as an antidepressant. Psychedelics are anti-inflammatory, score relatively high on physiological and psychological safety when used in a controlled setting, and in general, do not induce dependence.

In recent years, it has become clear that depression results from harmful structural and functional changes in brain circuits. Ketamine and psychedelics have proven effects as antidepressants, with ketamine already being used clinically. Psychedelics still have groundwork to be laid before clinical approval, as there are very few clinical trials that are well controlled, but new attention to this powerful class of drugs holds great promise. 

References:

 [1] Abdallah. “KETAMINE’S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS”  

2016 – Depression and Anxiety – Wiley Online Library.  Accessed 1 Nov. 2020.

[2] Qiao, Hui, et al. “Dendritic Spines in Depression: What We Learned from Animal Models.” Neural Plasticity, vol. 

2016, Hindawi, 10 Jan. 2016, p. e8056370, doi:https://doi.org/10.1155/2016/8056370.

[3] Govindarajan, Arvind, et al. “Transgenic Brain-Derived Neurotrophic Factor Expression Causes Both Anxiogenic 

and Antidepressant Effects.” Proceedings of the National Academy of Sciences, vol. 103, no. 35, National 

Academy of Sciences, Aug. 2006, pp. 13208–13. http://www.pnas.org, doi:10.1073/pnas.0605180103.

[4] Olson, David E. “Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics.” Journal of 

Experimental Neuroscience, vol. 12, SAGE Publications Ltd STM, Jan. 2018, p. 1179069518800508. 

SAGE Journals, doi:10.1177/1179069518800508.

[5] Scheuing, Lisa, et al. “Antidepressant Mechanism of Ketamine: Perspective from Preclinical Studies.” Frontiers in 

Neuroscience, vol. 9, Frontiers, 2015. Frontiers, doi:10.3389/fnins.2015.00249.

[6] Huang, Yu-Fei, et al. “Vascular Endothelial Growth Factor-Dependent Spinogenesis Underlies Antidepressant-like 

Effects of Enriched Environment.” Journal of Biological Chemistry, vol. 287, no. 49, American Society for 

Biochemistry and Molecular Biology, Nov. 2012, pp. 40938–55.

[7] Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Pandey SC, Pesold C, Roberts RC, Conley RR, Tamminga CA. Higher 

expression of serotonin 5-HT(2A) receptor in the postmortem brains of teenage suicide victims. Am J 

Psychiatry. 2002a;159:419–429

[8] Tang TZ, DeRubeis RJ, Hollon SD, Amsterdam J, Shelton R, Schalet B. Personality Change During Depression 

Treatment: A Placebo-Controlled Trial. Arch Gen Psychiatry. 2009;66(12):1322–1330. 

doi:10.1001/archgenpsychiatry.2009.166

[9] Muttoni, Silvia, et al. “Classical Psychedelics for the Treatment of Depression and Anxiety: A Systematic Review.” 

Journal of Affective Disorders, vol. 258, Nov. 2019, pp. 11–24. ScienceDirect, doi:10.1016/j.jad.2019.07.076

[10] Vollenweider, Franz X., and Michael Kometer. “The Neurobiology of Psychedelic Drugs: Implications for the 

Treatment of Mood Disorders.” Nature Reviews Neuroscience, vol. 11, no. 9, 9, Nature Publishing Group, 

Sept. 2010, pp. 642–51. http://www.nature.com, doi:10.1038/nrn2884.. 

[11] Pan, L., Hassel, S., Segreti, A., Nau, S., Brent, D., & Phillips, M. (2013). Differential patterns of activity and 

functional connectivity in emotion processing neural circuitry to angry and happy faces in adolescents with 

and without suicide attempt. Psychological Medicine, 43(10), 2129-2142. Doi:10.101

[12] Ly, C.; Greb, A. C.; Cameron, L. P.; Wong, J. M.; Barragan, E. V.; Wilson, P. C.; Burbach, K. F.; Soltanzadeh

Zarandi, S.; Sood, A.; Paddy, M. R.; Duim, W. C.; Dennis, M. Y.; McAllister, A. K.; Ori-McKenney, K. M.; Gray, J. A.; Olson, D. E. “Psychedelics Promote Structural and Functional Neural Plasticity” Cell Reports 2018, 23, 3170–3182.

Cover image from:

[13] Ly, C.; Greb, C. A.; Vargas, M. V.; Duim, W. C.; Grodzki, A. C. G.; Lein, P. J.; Olson, D. E. Transient Stimulation with Psychoplastogens is Sufficient to Initiate Neuronal Growth. ACS Pharmacol. Transl. Sci., 2020, ASAP.