Many people around the world deal with MDD (major depressive disorder) at some point in their life and often patients have relapses. Depression is recognized as a mental disorder that can escalate and affect many functions of a person's wellbeing and life. Unfortunately there is no absolute cure for this mental illness and currently therapies are the best form of cure. Surprising new data has emerged that suggests that ketamine, a popular drug used in parties, may actually have positive effects on a person's state of mind if they are diagnosed with or are experiencing depression-like symptoms. There has been little research done to prove or determine the extent of the cure for mental disorders like depression. As well there is uncertainty as to how to safely regulate and administer the use of this drug because of the history of drug abuse related to this specific drug.

I will be studying the neurological changes and effects of depression and ketamine. I'll start with a general understanding of the brain and its condition while it is under the pressure of depression and the unhealthy feeling of euphoria while on ketamine. Then I will be focusing on how ketamine affects depression and how it may be a plausable cure for depression, and why it may not be. There are many drawbacks and uncertainties around this cure, causing there to be debate as to whether it is worth using. Because of the complicated drug abuse history of ketamine, I will look into some social aspects and impacts of this and some obstacles with administering this antidepressant.

Ketamine is a dissociative anesthetic drug that produces a disorienting and hallucination effect on the user, allowing detachment from your environment and pain as well as loss of clarity in terms of senses such as sight and sound. When used as a party drug or for people who do not have the disorder, ketamine offers feelings of euphoria and disorientation which is why it’s popular at parties. Ketamine is technically a racemic mixture which means that it has both S-enantiomers and R-enantiomers.¹ Enantiomers are pairs of compounds with the same connectivity but structurally, they have opposite three-dimensional shapes. No two enantiomers are identical but they mirror one another, so they are very similar to each other.² Based on its structure and chiral center, there is a method that allows you to determine whether an enantiomer is R or S. If the line drawn from the chiral center is clockwise, it’s a R-enantiomer and if it is counterclockwise, it is a S-enantiomer.³ From this, S-enantiomers are the compounds that are thought to reduce depression. 

Depression or MDD (major depressive disorder) is a mental disorder that causes feelings of extreme sadness and dejection. Symptoms of depression include lack of energy, trouble concentrating, and loss of motivation among other things.⁴ Depression is related to changes in the brain's structure and function, specifically for areas of the brain that relate to emotions and thoughts. Parts of the brain such as the amygdala and subcortical regions overstimulate. The amygdala is related to emotions and emotional response and subcortical regions such as the hippocampus and thalamus. Along with the actual volume of the hippocampus becoming abnormally small, the neuron communication transfer efficiency and effectiveness significantly decreased. Smaller hippocampuses have been linked to be prone to relapsing.⁵ The main function for the hippocampus is managing memory and learning.⁶ When the volume of the hippocampus shrinks, it affects the functions of the hippocampus, resulting in learning and memory difficulties.⁵ The Prefrontal Cortex is also affected by depression. It is responsible for combining emotional information into actual decision-making thoughts but when under the stress of depression, the Prefrontal Cortex doesn’t work as well, therefore explaining the problems with concentration, negative thinking and the overall pessimistic mindset that is seen in correlation with depression. 

The neuroplastic characteristic of the brain allows it to change and adapt, and this is crucial when it comes to helping recover from depression. Neurons in the brain can develop to become stronger and protect themselves from stress factors, but this is a natural ability of the brain. Sometimes the brain is not able to adequately adapt through neuroplasticity, hence the purpose of antidepressants.⁷ Antidepressants are meant to increase the activity and efficiency of neurotransmitters in the brain. This is mainly for certain neurotransmitters such as serotonin, dopamine and norepinephrine which are significant reduced when the brain is in a depressive state.⁸ Made by the amino acid tryptophan, serotonin mainly is thought to regulate mood, along with many other jobs such as fine motor skills or sleeping and healing. Because serotonin plays such an important role in emotional thinking and moods, it can be very directly affected.⁹ Dopamine on the other hand can easily be confused with serotonin but dopamine mainly affects pleasure and motivation whereas serotonin mainly stabilizes moods.¹⁰ Also known as noradrenaline, norepinephrine is a specific kind of hormone and neurotransmitter that is in charge of your acute stress response, in other words your “fight or flight” response.¹² When there is a decrease in the number of these neurotransmitters, the aspects it is responsible for become weak, explaining the cause for many depression symptoms. 

There was also a hypothesis that states that ketamine may have the ability of NMDAR inhibition. NDMAR (N-Methyl-D-Aspartate Receptor) is a specific type of receptor in the brain, responsible for transmissions of glutamate. Glutamate is an excitatory neurotransmitter with amino acids that are involved in functions such as learning and memory.¹³ The earlier hypothesis proposed that ketamine may be able to inhibit NMDAR, either directly, selectively or just extra-synaptic receptors. By inhibiting this receptor, there will be an excessive release of glutamate, which will in turn sharpen the patient's learning and memory. There is also an understanding that ketamine is involved in AMPAR (Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors)  and it relates to ketamine’s antidepressant effects. AMPAR’s are responsible for managing excitatory neurotransmitters such as glutamate. Ketamine likely is able to increase the amount of glutamate release, allowing for better brain functions as a result. This is done mostly indirectly through disinhibition by reducing the amount of glutamate inhibitors such as NMDAR. When these glutamates are released, they enhance and activate AMPAR’s. These AMPAR’s then can lead to many other signalling pathways such as BDNF (Brain-Derived Neurotrophic Factor) which plays a crucial role in neuroplasticity. mTORC1 (Mechanistic Target of Rapamycin Complex 1) is also activated, and this plays a role in synaptic plasticity which contributes to antidepressant effects as well. There has also been recently developed research stating that there may be more to ketamine antidepressants which help with MDD. Mainly this is surrounding the idea that ketamine metabolizes, and because of this metabolization, there are other ways that ketamine may help depression, possibly without even affecting NDMAR’s. Ketamine can be metabolized with many other compounds in the body, one specifically is (2R,6R)-HNK. This compound has anti-depressant abilities of its own and ketamine is able to help battle depression through these compounds, which may have a completely separate pathway of its own. As well, ketamine metabolite (2R,6R)-HNK is able to affect another type of excitatory neuron called pyramidal neurons which in turn increase glutamate.¹³ 

When administering ketamine, the route of administration is very important. There are multiple methods that ketamine is able to enter the body such as oral, intramuscular, sublingual and intranasal. These methods are mainly considered because they require less clinical resources and have clear practical advantages for repeated dosing and patient comfort. Usually clinicals use intravenous (through the veins) because of availability and control while administering dosages.¹⁶ In 2019, ketamine administered through nasal spray was approved, specifically for treatment resistant depression (TRD). This is called esketamine (Spravato) and guidelines state that it can only be taken under the supervision of a health care practitioner and the patient has to be watched over for sometime afterwards. One research study was done to test the effectiveness of esketamine as short-term treatment. The results showed a significant decrease in depression for the group that was given ketamine as compared to the group given the placebo (as a note, both groups continued to take their regular antidepressants).¹⁴ It is found that esketamine provides relief from treatment-resistant depression within 40 minutes and can very effectively for up to 24 hours. One study found that esketamine (plus regular antidepressant) helped people for up to 16 weeks into the treatment.¹⁴

Though ketamine proves to be a plausible antidepressant, most of its complications lie within its dissociative and hallucinogenic effects on the human body. Commonly, ketamine is known as “Special K”, “angel dust” or other slang because it is a popular party drug. When used it produces pain control, forgetfulness, intoxication, disassociation, and euphoria.¹⁴ All of this introduces many complications and struggles to safely administer the drug while ensuring it does not get abused for its euphoric sensations. There is a struggle to find the silver lining and trust in the patients for this drug, which is why it isn’t exclusively being prescribed. When administering or prescribing ketamine, there is caution around patients that are; 

1. Patients with psychosis or schizophrenia because of ketamine may affect these mental illnesses negatively due to its dissociative properties. 
2. People with a history of substance abuse
3. Teenageres because of some concerns around ketamines effects on developing brains. 
4. Pregnant or breastfeeding women 
5. Older adults with symptoms of dementia 

There has been some conversation for creating a similar drug as ketamine but with less negative effects, though this idea has mostly not been entertained as much.¹³ As well there is some concern that, with repetitive dosing, the patient may become less effective and will start to require larger doses.¹⁴ Hallucinogen Persisting Perception Disorder (HPPD) has been reported several weeks after ketamine use as well which means that ketamine may have some unwanted side effects, though there is more research needed to objectively prove this.¹⁵ 

Currently ketamine is not one of the first options to treat depression and is mainly used for high risk depressive stages such as TRD or suicidal depression. The FDA (US Food and Drug Administration) and the EMA (Europeans Medicines Agency) have both approved ketamine for TRD.¹ Still there is hesitation to open more access to the drug and some mistrust around private clinics opening up that are able to administer ketamine.¹

In conclusion I think there is a large scope for ketamine to help with depression for many patients medically. The drug has effective results on depression and is able to battle NMDAR well for the better release of glutamate in the brain. But because of the many complications and lack of research, there are uncertainties and questions about prescribing and administering ketamine and to what extent. I think using it for TRD is helpful, especially since it is one of the only antidepressants with significant positive impacts on TRD or suicidal depression and therefore, it should be used to help the patient as much as possible. There will likely need to be societal changes and many precautions taken before ketamine can be administered to depressive patients exclusively and with more ease.

1. https://medicine.yale.edu/news-article/ketamine-handle-with-care/ 
2. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Fundamentals/Isomerism_in_Organic_Compounds/Enantiomers 
3. https://chem.libretexts.org/Bookshelves/General_Chemistry/Book%3A_Structure_and_Reactivity_in_Organic_Biological_and_Inorganic_Chemistry_(Schaller)/I%3A__Chemical_Structure_and_Properties/05%3A_Stereochemistry/5.05%3A_Simple_Organic_Enantiomers-_R_and_S_configurations 
4. https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007#:~:text=Although%20depression%20may%20occur%20only,as%20back%20pain%20or%20headaches 
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC3619732/#:~:text=The%20main%20subcortical%20limbic%20brain,have%20neurotrophic%20effects%20(32) 
6. https://my.clevelandclinic.org/health/body/hippocampus 
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC7864313/#:~:text=In%20depression%20there%20are%20hyperactivity,the%20efficiency%20of%20synaptic%20transmission 
8. https://www.camh.ca/en/health-info/mental-illness-and-addiction-index/antidepressant-medications#:~:text=What%20do%20Antidepressant%20Medications%20do,symptoms%20of%20depression%20and%20anxiety 
9. https://www.healthline.com/health/mental-health/serotonin#functions 
10. https://www.healthline.com/health/mental-health/serotonin#serotonin-boosters 
11. https://my.clevelandclinic.org/health/articles/22610-norepinephrine-noradrenaline  
12. https://my.clevelandclinic.org/health/articles/22839-glutamate 
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC5999402/ 
14. https://www.health.harvard.edu/blog/ketamine-for-treatment-resistant-depression-when-and-where-is-it-safe-202208092797 
15. https://www.dea.gov/factsheets/ketamine 
16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715255/ 

I would like to acknowledge this to my teacher, Mrs. Calvert who helped facilitate and manage our projects and helped me kickstart a CYSF Science Fair Club at my school. I would also like to acknowledge my principle, Mrs. McAllister who supported my idea for a club and involvment in the fair.