Ketamine For Depression

Depression is common and can be expressed in a variety of symptoms. In those suffering from depression, brain cells can decrease in size, connections between brain cells can be dysfunctional, and some brain networks such as the default mode network can be overactive. These changes reflect the often negative self-focused ruminative thought patterns that can occur in those who suffer from depression. Ketamine can rapidly and safely reverse these changes. Ketamine assisted therapy has been shown to lead to long-lasting changes in many people suffering from symptoms of depression.


Depression is a serious illness and one of the leading causes of disability worldwide26,43,46. The World Health Organization estimates that globally 5% of adults suffer from depression15. The National Institute of Health reports that in the United States over 8% of the adult population, 21 million people, have suffered at least one major depressive episode42. There is no lab test or imaging study to diagnose depression the way we might diagnose a physical illness such as a heart attack or asthma. As a mental illness, depression can be more difficult to identify. Depression is a constellation of symptoms that includes, among others: feelings of sadness or emptiness, difficulty sleeping, rapid weight change, fatigue, lack of concentration, and an enduring sense of worthlessness or guilt5.

Despite the overwhelming number of people who battle depression daily, the field of mental health has struggled to provide adequate treatment. Prevailing research has shown that up to one-third of patients diagnosed with depression will not improve even after treatment with up to four different antidepressants59. This occurrence is called treatment resistant depression7. Treatment resistant depression is debilitating not only because of the hopelessness it contributes to, but also because depression and chronic stress have been shown to change the structure, function, and development of the brain1,12,20,61,65. Both chronic stress and depression lead to dysfunctional connections between and decreased size of some brain cells, alteration in the body’s stress hormone system, and changes in the shape and structure of the brain and its networks3,20,21.

van Ettinger-Veenstra H, Lundberg P, Alföldi P, Södermark M, Graven-Nielsen T, Sjörs A, Engström M, Gerdle B. Chronic widespread pain patients show disrupted cortical connectivity in default mode and salience networks, modulated by pain sensitivity. J Pain Res. 2019 May 29;12:1743-1755. doi: 10.2147/JPR.S189443. PMID: 31213886; PMCID: PMC6549756.

Depression and Brain Networks

When multiple areas of the brain communicate and work together, this is called a brain network47,56. Different networks come online for different tasks and situations we encounter. Data from brain imaging shows that chronic stress and depression change the activity and communication of several brain networks23,39,40,55,65,69,75. The salience network (SAL), affective network (AN), cognitive control network (CCN), central executive network (CEN), and default mode network (DMN) are all affected by depression and chronic stress 10,30,74. Of particular interest for those suffering from symptoms of depression, the default mode network seems to become more active and larger in size than those without symptoms of depression11,23,40,48,61,65,69,75.

The default mode network is active when a person does not have a goal oriented task56. This network seems to be responsible for creating our inner monologue, remembering past experiences, and daydreaming23,55,68,75. In people who suffer from depression, their brain networks seem to favor rumination and self-critical introspection rather than processing, interacting, and interpreting outside information23,55,56,65,69,75. In this way, those who suffer from depression have an inner monologue that is more likely to be negative, self-critical, and ruminatively self-focused39,40.

Depression and Brain Receptors

For over 60 years theories of depression have focused on the monoaminergic system9,32,37. Enormous amounts of research have led to the development of SSRI’s and SNRI’s that act on that system. Yet these treatments are still hampered by limited effectiveness, slow onset, and bothersome side effects35,53,53. Recently, researchers have shifted their attention to look at medications that primarily affect a different system, the glutamate neurotransmitter system21,25. One of the more promising of these medications is ketamine.

In light of the cellular and network changes that occur in those suffering from depression and chronic stress, researchers began to target the glutamate neurotransmitter system with medications like ketamine. Ketamine binds to several different receptors in the brain including serotonin, dopamine, opioid, nicotinic and muscarinic receptors70,71. However, it seems its main neurochemical antidepressant activity occurs at the N-methyl-D-aspartate (NMDA) receptor71. Receptors are kind of like switches on the outside of a cell. When these switches are activated, a cascade of changes occur within cells. Sometimes these changes include release of molecules that can cause changes to other cells like stimulating growth or promoting communication.

Ketamine as Treatment for Depression

The activity of ketamine in the brain is very complicated. Ketamine interacts with many different receptors in different parts of the brain. One important interaction seems to be that ketamine turns off a cell that stops the activity of another cell; it essentially turns off the brake. This causes a cascade of transmitters, including glutamate, in specific areas of the brain. This cascade causes changes in brain cells that promote brain cell growth and the formation of new connections between brain cells. This creates “neuroplasticity,” the ability of the brain to change its structure and connectivity. Ketamine promotes neuroplasticity and actually reverses some of the detrimental changes caused by the symptoms of depression and chronic stress described above 2,3,6,12,19,20,24,34,35,41,71.

Studies have consistently demonstrated that ketamine safely, rapidly, and robustly decreases symptoms of depression4,8,13,16,31,50,51,53,57,63,72,73. Even a single infusion of ketamine seems to turn down the hyperactive default mode network in patients suffering from symptoms of depression and normalizes activity in other brain networks1,10,23,49,60–62,65,69. Additionally, ketamine has been shown to rapidly reduce suicidal ideation17,51,54,67,72 and also seems to normalize circadian rhythm, potentially improving sleep in those suffering from symptoms of depression22,35.

Of note, the majority of studies investigating ketamine as treatment for depression do not reference forms of therapy beyond ketamine administration in their protocols. The period of increased neuroplasticity after ketamine administration creates an advantageous milieu for psychotherapy14,24,29,33,36–38,45,64. Indeed, ketamine assisted therapy has been shown to bring a more long-lasting reduction in symptoms of not only depression, but also post-traumatic stress disorder (PTSD), anxiety, chronic pain disorders, and substance use disorder18,27,28,31,33,44,52,58,66.


The symptoms of depression are varied. The underlying causes of these symptoms are often complex. There are changes in the brains and bodies of people suffering from symptoms of depression. Ketamine seems to reverse some of the changes in the brain by promoting neuroplasticity. When ketamine is paired with therapy, these changes become much more transformative and long-lasting.


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