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Low Doses of Ketamine as a Rapid Antidepressant

Post by Maeve (BISC 4532 - Spring 2024)

One of the most prevalent mental health disorders in the United States is depression. The CDC reported that over 18%, almost 1 in 5, Americans reported having ever been diagnosed with depression, making it a highly prevalent issue. One of the most common treatments for depression are Selective Serotonin Reuptake Inhibitors (SSRI), which selectively inhibit the reuptake of serotonin, leading to excess serotonin in the synapses. While effective, SSRIs can have hefty side effects, such as nausea, headaches, and symptoms of serotonin syndrome. Additionally, SSRIs must be taken for several weeks before the patient begins to feel a reduction in depressive symptoms. So, what if a different drug had a more immediate therapeutic effect? 

A study done on the effect of ketamine on MDD symptoms revealed that therapeutic effects of depression treatments may be able to come to fruition much sooner than possible with standard SSRI treatments. 

68 participants with treatment-resistant MDD or bipolar disorder were weaned off any medication and were given either a ketamine and placebo infusion two weeks apart, with the order of each injection being randomized between participants. This was a double blind study, meaning neither the patient nor investigators, nursing staff, or clinical raters were aware of which solution the patient was given. 

To measure symptoms, the MADRS was used to assess depressive symptoms and the MADRS5 was used to assess the symptoms associated with typical symptoms. The Structured Interview Guide for the clinician-administered Hamilton Depression Rating Scale–Seasoned Affective Disorder Version (SIGH-SAD), specifically the Scale for Atypical Symptoms (SAS), was used to assess the symptoms associated with atypical depression. Examples of these symptoms include social withdrawal, weight gain, increased appetite, and hypersomnia. 

The ketamine infusion resulted in statistically significant improvements in symptoms detected in the MADRS (typical symptoms), specifically pessimistic thoughts, sadness, and inability to feel. Additionally, the ketamine infusion resulted in statistically significant improvements in symptoms detected in the SAS (atypical symptoms), specifically carbohydrate craving, social withdrawal, and fatigability. 

At the day 3 mark following the ketamine administration, statistically significant improvements in typical and atypical symptoms such as reported sadness, inability to feel, concentration difficulties, apparent sadness, social withdrawal, carbohydrate craving, and fatigability. Over the three day interval consistent improvements were made among the symptoms. 

The results of this study indicate that ketamine appears to rapidly alleviate symptoms, and is most rapidly able to alleviate symptoms of typical depression. Typical symptoms were significantly improved after just one day post ketamine administration, and atypical symptoms had nearly the same levels of alleviation after three days post ketamine administration.

So, what about the mechanisms behind ketamine make it such a fast acting antidepressant?

A study done with 58 participants with major depressive disorder investigated mechanisms related to ketamine’s rapid antidepressant effects. In this study, ketamine was found to increase functional connectivity in the VS-left dorsolateral prefrontal cortex and DC-right ventrolateral prefrontal cortex. These effects were specific to the fronto-striatal circuitry. Post-ketamine, increased C-reactive protein were correlated with decreased VRP-right orbitofrontal cortex functional connectivity. 

Fronto-striatal interactions have been shown to be significantly associated with motivational behavior, and the findings of this study suggest that depressive symptoms may be due to a lack of interaction between these regions. Ketamine’s impact on functional connectivity may be what is alleviating these depressive symptoms, meaning that ketamine may increase cognitive flexibility as well as modulation over reward processes. This, in turn, may be what is providing therapeutic effects on depressive symptoms. 

What can this tell us about ketamine, and the larger discussion surrounding antidepressants as a whole? 

Firstly, it is important to note that these studies are preliminary and should be interpreted with caution, as they are very preliminary. The role of ketamine as an antidepressant is still largely unknown in terms of its specific neural mechanisms, and the results of preliminary studies require further understanding before a drug like ketamine can be regularly used in a clinical setting.

Additionally, ketamine is a highly abused drug that can have negative side effects such as dissociative effects and an addictive potential. Considering these concerns, further research regarding administering ketamine as a fast acting antidepressant is needed.

Despite these necessary cautions, the results of these studies present exciting knowledge related to treatments for depression. With such a high prevalence across the population, effective therapeutic treatments for depression are needed, and the possibility of a fast acting drug to alleviate symptoms is promising. Upon further knowledge and research, it is possible that low, initial doses of ketamine may be able to act as a clinically administered rapid antidepressant. 

Sources:

Mkrtchian, A., Evans, J. W., Kraus, C., Yuan, P., Kadriu, B., Nugent, A. C., Roiser, J. P., & Zarate, C. A., Jr (2021). Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Molecular psychiatry, 26(7), 3292–3301. https://doi.org/10.1038/s41380-020-00878-1

Park, L. T., Luckenbaugh, D. A., Pennybaker, S. J., Hopkins, M. A., Henter, I. D., Lener, M. S., Kadriu, B., Ballard, E. D., & Zarate, C. A., Jr (2020). The effects of ketamine on typical and atypical depressive symptoms. Acta psychiatrica Scandinavica, 142(5), 394–401. https://doi.org/10.1111/acps.13216

https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm