Ketamine for Depression

Updated: Aug 22, 2018

By Dylan Cooper

Depression affects about 17% of the population and can have devastating effects on those who suffer from it. Currently, there are many treatment options but the efficacy of these treatments is limited. Some significant flaws associated with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) include low response rates, treatment resistance, and a significantly long onset to take effect (Trivedi et al., 2006). Therefore, it is currently of widespread interest and benefit to find new classes of drugs that are more effective and faster at treating this devastating illness.


Research and clinical studies have shown that the stress associated with depression leads to neuronal atrophy in brain regions that are associated with mood and emotion. Specifically, a reduction in the number of synapses on dendritic spines, which are key points of communication between neurons (Duman, 2006). Two of the main mechanisms that are thought to be responsible for depression are the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the monoamine hypothesis. Recent research however, has shown that other mechanisms are at work. Specifically, it has been shows that depression is associated with disruptions in neurotrophic/growth factors which have been found to be involved in this atrophy of dendritic spines in those who suffer from depression (Duman, 2016).


Of recent interest is the effectiveness of ketamine, an anesthetic, in depression. Ketamine is unique in that it produces rapid improvement in mood in patients who are resistant to treatment to currently available antidepressants (Berman et al., 2000). In addition, this rapid improvement is sustained. The mechanism of action of ketamine is very different from the antidepressants found on the market today. Specifically, ketamine is an NMDA receptor antagonist. NMDA receptors are a type of glutamate receptor. The fact that ketamine produces such a rapid and efficacious response directly challenges the monoamine hypothesis of depression. This is because the monoamines serotonin, norepinephrine as well as the HPA axis are not directly influenced by ketamine. Research has found that the efficacy of ketamine for depression depends on its ability to induce the creation of new synapses and reverse synaptic atrophy (Duman, 2006). Because of this, understanding the mechanisms by which ketamine does this is could be the key to unraveling new targets in the brain for treating depression.


Of the parts of the brain affected by depression, two key regions that are the pre-frontal cortex and hippocampus. Studies have shown that there is a decrease in neuronal cell body size, atrophy of neural processes as well as a reduction in the number of glial cells in this area of the brain (Drevets, Price, & Furey, 2008). Glial cells are the masked heroes of the nervous system, providing metabolic and nutritional support for neurons and their reduction in number could play a role in this neuronal atrophy. In contrast, other studies have shown hypertrophy (an increase in size) of neurons in the amygdala, a part of the brain responsible for emotional responses (Roozendaal, McEwen, Chattarji, 2009).


Another mechanism that is currently being studied in those with depression is the role of neurotrophic factors. Neurotrophic factors play a very important role in the brain, specifically, their functions include facilitating neuronal maturation and survival. One particularly important neurotrophic factor is Brain Derived Neurotrophic Factor (BDNF). It is one of the most highly expressed neurotrophic factors in the brain (Duman, 2011). In depressed subjects, blood levels of BDNF have been shown to be decreased. (Schmidt, Shelton, & Duman, 2011). The way that Ketamine reduces depressive symptoms is through the rapid induction of the number of spine synapses in the pre-frontal cortex. Studies have shown that just two hours after a single dose of ketamine, there is an increase in synapse number, which corresponds to the initial improvement of depressive symptoms (Behrens, Ali, & Dao, 2007). The mechanism that underlies this is thought to be through the phosphorylation and activation of mammalian target of rapamycin complex 1 (mTOR1) and related signaling proteins.


The antidepressant actions of ketamine require BDNF which is linked to this process. Blockade of NMDA receptors by ketamine specifically on GABA-ergic neurons is thought to result in disinhibition of glutamate transmission (Duman 2014). This causes a burst of glutamate release which is thought to increase BDNF release as well as activate mTOR signaling (Duman 2014). It is through this mechanism that the synthesis of synaptic proteins required for synapse formation are increased. This allows new connections to form in the PFC as well as other mood related brain areas. These exciting studies involving ketamine have the potential for uncovering an entirely new class of antidepressants! This new class of antidepressants would have a novel mechanism with a rapid antidepressant response and take the whole pharmaceutical industry in a new direction regarding antidepressant treatment.


References:


Duman R, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116-1127.


Behrens M, Ali SS, Dao DN, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007;318:1645-1647.


Berman R, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.


Drevets W, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depres- sion. Brain Struct Funct. 2008;213:93-118.


Duman, R. S. (2014). Neurobiology Of Stress, Depression, And Rapid Acting Antidepressants: Remodeling Synaptic Connections. Depression and Anxiety, 31(4), 291-296. doi:10.1002/da.22227


Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009;10:423-433.


Schmidt H, Shelton RC, Duman RS. Functional markers of depression: diagnosis, treatment and pathophysiology. Neuropsychopharmacology. 2011;36:2375-2394.

Trivedi M, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.

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