Search
  • Mignon Walker MD

Treat the Cause, Not the Symptoms

Ketamine is popping up everywhere as an effective, rapid, life changing intervention for treatment resistant depression, chronic nerve pain, PTSD, and fibromyalgia.


Ketamine’s antidepressant function works through a different mechanism than other medications used for depression. Conventional medications increase levels of naturally occurring neurotransmitters (nerve communication molecules) such as serotonin, norepinephrine and dopamine. These chemicals relay messages between brain cells. The theory is that having greater quantities of these neurotransmitters positively affects mood.


Ketamine works in a similar fashion, by increasing a brain messaging molecule, but unlike other antidepressants it increases levels of glutamate, the most abundant chemical messenger in the brain. The result? A greater impact on more brain cells at one time.




Common antidepressants are slow-acting and have unpleasant side-effects. It often takes several weeks to make a noticeable difference in how people with depression feel and over the course of therapy may leave you impotent, overweight and with unpleasant brain fog. On the other hand, ketamine immediately impacts brain cells, potentially offering relief from depressive symptoms within hours with a more tolerable side effect profile.

"I’ve never laughed as much as I have these past six weeks." --real patient, CR

Over the past two decades, numerous studies have consistently demonstrated that ketamine rapidly reduces depressive symptoms when given intravenously. Much of this work has been carried out in the NIMH Intramural Research Program (IRP) on the NIH campus in Bethesda, Maryland, where there are about 600 scientists conducting research on everything from basic neuroscience to clinical trials.


Does it work?


Many published and unpublished studies from around the world examining the use of ketamine for treatment-resistant depressive disorders have reported positive results in both the short and the long term. Average response rates are approximately 70%, and remission rates are 30–50%. The response rates for the less chronic conditions are higher.


In 2006, for the first time in patients, Dr. Zarate and colleagues found that ketamine produced rapid, robust, and relatively sustained antidepressant effects in patients with treatment-resistant depression (in this study, patients had failed over six antidepressants). Since then, among the key findings carried out at NIMH by Dr. Zarate are the findings that ketamine has strong, rapid effects on treatment-resistant depression and bipolar depression, as well as in reducing suicidal thoughts.


Research suggests that untreated depression causes long-term brain damage and is a risk factor for dementia. Studies show that people with depression have up to 20% shrinkage of the hippocampus, a region of the brain critical for memory and learning. In the early stages of illness, these losses are reversible, and treatment with ketamine rapidly increases the number and quality of these connections. It appears that the brain’s capacity to heal diminishes with repeated bouts of illness. Animal studies indicate that connections between brain cells diminish under chronic stress, but ketamine reverses these stress-related changes. Ketamine is different than any other antidepressant in that it not only prevents the neurotoxic effects of depression on the brain, but it also seems to have a growth-promoting effect.


For many patients, a depressive illness is a chronic relapsing condition. The first episode often has a clear environmental trigger, but thereafter, the amount of stress required to cause a relapse seems to decrease. In bipolar depression, those with untreated or partly treated episodes progress particularly poorly, with their bouts of illness becoming more severe and closer together over time. This suggests that for some, treating early and aggressively may prevent a deteriorating course.


Most commonly used antidepressants, the SSRIs (selective serotonin reuptake inhibitors like citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)), frequently cause undesirable side effects, including insomnia, weight gain, sexual dysfunction, and brain fog— which can lead to patients either under-dosing or discontinuing their treatment. Ketamine on the other hand does not have the same side effect profile. This means that it may be used either alone to help those who experience these side effects, or in combination with lower doses of the current antidepressants, thus making them more tolerable. Similarly, by improving the outcomes of psychotherapy, ketamine may be able to reduce the time and expense of this treatment. Of note, concurrent psychotherapy while receiving ketamine therapy is recommended.


Ketamine for Chronic Pain Relief

A wide body of evidence demonstrates ketamine’s use as a painkilling agent. This evidence has been a catalyst for ketamine’s adoption as a medicinal intervention. One breakthrough 2012 study published in the British Journal of Clinical Pharmacology found that ketamine was effective as a strong analgesic. In patients suffering from neuropathic pain states, ketamine infusion resulted in “long-term” pain relief for up to three months following treatment. The study called for further research into the risks and benefits.


Ketamine for PTSD

A breakthrough 2014 study in JAMA Psychiatry discovered that a single intravenous subanesthetic dose of ketamine resulted in “significant and rapid reduction in PTSD symptom severity.”

Over the past few years, many articles and news reports have heralded ketamine as a potential wonder drug for treating PTSD. A recent article published by Medscape for example, discussed how a team of researchers at the Icahn School of Medicine at Mount Sinai in New York City successfully used ketamine to fight depressive symptoms in patients with PTSD and severe depression. Ketamine prevented the onset of PTSD in a mouse model, as well as the tendency for the mice to freeze when returned to their enclosures.



Ketamine for Anti-Inflammation

A 2016 paper in the medical journal Acta Pharmacologica Sinica found that ketamine had strong anti-hyperalgesia and anti-inflammatory properties. This is especially important in the field of medical research because inflammation, particularly inflammation of key internal organs, is known to cause several chronic illnesses and to co-occur with cancers.

Patients that receive ketamine infusion therapies not only benefit from its antidepressant and pain-killing effects, but they also enjoy reduced organ inflammation. In doing so, ketamine infusion recipients are less at-risk of chronic disease and other illnesses. By contrast, other frontline medications have the potential to increase or catalyze internal inflammation.

Ketamine Is Well Tolerated

One of ketamine’s key benefits demonstrated in the aforementioned studies is that it is well-tolerated in conjunction with other frontline pain and depression treatments. Although it is contraindicated for use with the benzodiazepine class of drugs, ketamine is compatible with SSRI, SNRI, and other non-narcotic anti-anxiety and antidepressant drugs.

There are also relatively few long-term side effects of ketamine use. In high doses, there are reported short-term effects including psychedelic symptoms (including hallucinations and memory defects). However, unlike SSRI antidepressants, there are no long-term negative side effects like sexual dysfunction, lethargy, or anhedonia.



References


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.


Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R. C., … Drevets, W. C. (2018). Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 75, 139-148.


Diaz Granados, N., Ibrahim, L. A., Brutsche, N. E., Ameli, R., Henter, I. D., Luckenbaugh, D. A., … Zarate, C. A. Jr. (2010). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychiatry, 71, 1605-11.


Diaz Granados, N., Ibrahim, L., Brutsche, N. E., Newberg, A., Kronstein, P., Khalife, S., … Zarate, C. A. Jr. (2010). A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry, 67, 93-802.


Kraus, C., Wasserman, D., Henter, I. D., Acevedo-Diaz, E., Kadriu, B., & Zarate, C. A. Jr. (In Press). The influence of ketamine on drug discovery in depression. Drug Discovery Today. doi: 10.1016/j.drudis.2019.07.007


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, 774-778.


Singh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., … Van Nueten, L. (2016). Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biological Psychiatry, 80, 424-431.


Trullas, R., & Skolnick, P. (1990). Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. European Journal of Pharmacology, 185, 1–10.


Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G.I., … Gould, T. D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533, 481-486.


Zarate, C. A. Jr., Singh, J. B., Carlson, P. J., Brutsche, N.E., Ameli, R., Luckenbaugh DA, … Manji, H. K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63, 856-64.




6 views0 comments