Treating the causes of depression
Could NAD+ and ketamine treatment work together to tackle depression? In this article, we dive into the latest scientific evidence to answer this crucial question.
With around 1 in 12 US adults experiencing at least one episode of major depression each year (National Institute of Mental Health, 2022), finding safe and effective ways to treat this debilitating or even lethal condition is vitally important.
The causes of depression in each individual are complex. Key factors include stressful life events, lack of social support, early life experiences, and challenging patterns of thinking about ourselves and the world (Roy & Campbell, 2013).
However, treatments that modify our brain chemistry, such as antidepressants, can be an essential part of the solution for some people.
Improving on traditional antidepressants
Scientists have spent many decades studying what happens in the brain when someone is experiencing depression. Over this time, a number of important theories have been put forward about what chemicals in the brain are involved in depression and how it might be treated (Roy & Campbell, 2013).
One influential theory argues that levels of “monoamine” signaling molecules such as serotonin are lower in the brains of people experiencing depression (Dell’Osso et al., 2016). To help treat this, antidepressant drugs that increase levels of serotonin, such as Prozac, were developed. These are the most commonly prescribed form of antidepressant today.
While these drugs are a lifeline to many people, it’s clear that they are rarely a “cure” by themselves. They take weeks to reach their full effect and for some people, they don’t work at all. New and better treatments for depression are urgently needed.
Can ketamine treatment help depression?
Compared to slow-acting traditional antidepressants, startling scientific evidence from studies of ketamine treatment have shown that it can relieve the symptoms of depression immediately (Berman et al., 2000; Krystal et al., 2019). Effects from a single dose can last up to 2 weeks.
What’s more, ketamine can even be effective for some people who haven’t gotten any benefit from traditional antidepressants, with an improvement in depressive symptoms seen in 50%–75% of treatment-resistant patients (Wilkinson et al., 2017).
Ketamine can be taken regularly using an FDA-approved nasal spray called Spravato, or by intravenous (IV) injections at a clinic.
How does ketamine work?
One way in which ketamine may reduce depression is by modifying “glutamatergic” signaling in the brain. Ketamine acts directly on the glutamatergic signaling system to change brain chemistry and increase brain plasticity (Krystal et al., 2019).
Brain plasticity is the ability of the brain to rewire itself based on our experiences. For those suffering from depression, the boost in rewiring after taking ketamine could help the brain to learn better ways of relating to ourselves, others, and the world.
Another way that ketamine might treat depression is by reducing inflammation (Beurel et al., 2020), which is an immune reaction that causes a part of the body to swell in response to stress or damage — think of a swollen ankle after a fall. Many people with depression show a long-lasting increase in inflammation, including within the brain itself.
How can boosting NAD+ support ketamine treatment?
How does ketamine help to reduce inflammation? It turns out that ketamine acts on the “kynurenine pathway” in the brain (Kopra et al., 2021), which is responsible for synthesizing the helper molecule (coenzyme) NAD+ from tryptophan found in protein in our diet.
Ketamine and NAD+ are both important for keeping the kynurenine pathway in a healthy “neuroprotective” mode that guards brain cells against damage (Ogyu et al., 2018). When this pathway gets out of balance, brain cells are exposed to harmful “oxidative stress”, which can lead to inflammation and depression.
Some scientists believe that a root cause of a range of mental health disorders, including depression, is depletion of NAD+ stores in cells (Morris et al., 2020). This lack of NAD+ leads to “bioenergetic failure” — causing increased oxidative stress, inflammation, and potentially depression.
Keeping NAD+ stores topped up could therefore be an important defense against depression. Along with natural ways of boosting NAD+, both NAD+ supplements and intravenous (IV) NAD+ injection have been proven to be effective ways of raising NAD+ levels in the body (Grant et al., 2019; Yoshino et al., 2021).
Combining NAD+ and ketamine treatment for depression
In combination, NAD+ and ketamine treatment could help to treat depression by reducing oxidative stress and inflammation. The kynurenine pathway seems to be the critical link between the two, and scientists are continuing to study its role in depression (Ogyu et al., 2018; Kopra et al., 2019)
As this research progresses, traditional antidepressants targeting the serotonin system are being complemented by novel approaches, such as NAD+ and ketamine treatment. Building on the hard work of many scientists, these breakthrough treatments are offering new hope to people worldwide who suffer from depression.
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351-354. https://doi.org/10.1016/S0006-3223(99)00230-9
Beurel, E., Toups, M., & Nemeroff, C. B. (2020). The bidirectional relationship of depression and inflammation: double trouble. Neuron, 107(2), 234-256. https://doi.org/10.1016/j.neuron.2020.06.002
Dell’Osso, L., Carmassi, C., Mucci, F., & Marazziti, D. (2016). Depression, serotonin and tryptophan. Current Pharmaceutical Design, 22(8), 949-954. https://doi.org/10.2174/1381612822666151214104826
Grant, R., Berg, J., Mestayer, R., Braidy, N., Bennett, J., Broom, S., & Watson, J. (2019). A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. Frontiers in Aging Neuroscience, 11, 257. https://doi.org/10.3389/fnagi.2019.00257
Kopra, E., Mondelli, V., Pariante, C., & Nikkheslat, N. (2021). Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review. Journal of Psychopharmacology, 35(8), 934-945. https://doi.org/10.1177/02698811211026426
Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: a paradigm shift for depression research and treatment. Neuron, 101(5), 774-778. https://doi.org/10.1016/j.neuron.2019.02.005
Morris, G., Walder, K. R., Berk, M., Marx, W., Walker, A. J., Maes, M., & Puri, B. K. (2020). The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?. Molecular Biology Reports, 47(7), 5587-5620. https://doi.org/10.1007/s11033-020-05590-5
National Institute of Mental Health (2022). Major depression. National Institute of Mental Health. Retrieved February 24, 2022, from https://www.nimh.nih.gov/health/statistics/major-depression
Ogyu, K., Kubo, K., Noda, Y., Iwata, Y., Tsugawa, S., Omura, Y., … & Nakajima, S. (2018). Kynurenine pathway in depression: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews, 90, 16-25. https://doi.org/10.1016/j.neubiorev.2018.03.023
Roy, A., & Campbell, M. K. (2013). A unifying framework for depression: bridging the major biological and psychosocial theories through stress. Clinical and Investigative Medicine, E170-E190. https://doi.org/10.25011/cim.v36i4.19951
Wilkinson, S. T., Toprak, M., Turner, M. S., Levine, S. P., Katz, R. B., & Sanacora, G. (2017). A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. American Journal of Psychiatry, 174(7), 695-696. https://doi.org/10.1176/appi.ajp.2017.17020239
Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., … & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229. https://doi.org/10.1126/science.abe9985