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Transformed by the Renewing of Your Mind.

Ketamine

A. What is Ketamine?

Ketamine was first synthesized in 1962 by Dr. Calvin Stevens of Wayne State University while at Park Davis Laboratories. His work at the time was investigating an alternative anesthetic to phencyclidine (PCP), less likely to cause seizures or neurotoxicity. As such, ketamine is a dissociative anesthetic, and produces anesthesia through hallucinogenic, amnestic, analgesic, sedative, and cataleptic effects. Ketamine has been used extensively as an anesthetic and sedative agent in both human and veterinarian medicine. It gained popularity in the 1970's in battlefield and burn medicine settings. In the perioperative setting it has many functions including but not limited to induction for anesthesia in trauma and burn patients. As a sedative for patients that require awake fiberoptic intubation and to relieve pain in patients that require hip surgery before performing spinal anesthesia. For more than 50 years ketamine has proven to be a safe anesthetic drug with potent analgesic properties.

B. How does Ketamine treat depression?

Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex (PFT) and the hippocampus and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits although typical antidepressants have limited efficacy and delayed response times of weeks to months. Ketamine, a N-methyl-D-aspartate receptor antagonist produces rapid within hours antidepressant responses in patients who are resistant to typical antidepressants. Ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress.

C. How does Ketamine treat chronic pain?

Over the past decades, there has been a growing number of patients being diagnosed with some form of chronic pain[1]. The treatment of chronic pain is based on a trial and error approach with antidepressants, anti-epileptics and opiods as drugs of first choice. Irrespective of treatment, efficacy is limited with just 30-40% of patients showing adequate to good pain relief. Anesthesiologists and other pain physicians started using ketamine at subanesthetic doses, to treat therapy-resistant chronic pain syndromes.  Low dose ketamine produces strong analgesia by inhibition of the N-methyl-D-aspartate receptor.  Other mecanisms by which ketamine inhibits pain include enhancement of descending inhibition and anti-inflammatory effects in the brain.

At KHWCT we practice a multimodal approach to treating patients with treatment resistant depression and chronic pain. We collaborate with psychiatrists, neurologists, mental health providers, physical therapists, family medicine physicians, pain specialists, and obstetricians/gynecologists to help develop the best treatment plan for each patient. Scientific research supports that exercise, diet and proper rest are integral components to health and wellness. We treat patients on a referral basis and are happy to assist you.

Articles

Signaling Pathways Underlying the Rapid Antidepressant Actions of Ketamine
Author(s): Ronald S. Duman, Nanxin Li, Rong-Jian Liu, Vanja Duric, and George Aghajanian
Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These studies identify new targets for rapid acting antidepressants that are safer than ketamine.

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Maintenance Ketamine Treatment Produces long-term Recovery from Depression
Author(s): Michael M. Messer, MD, and Irina V. Haller, PhD, MS
Patients not responding to conventional treatment for depression are classified as having treatment-resistant depression (TRD). Electroconvulsive therapy is effective in ~50% of the patients diagnosed with TRD. Recent reports of rapid antidepressant effect with a single dose of ketamine suggest a potential benefit for TRD patients. However, there are no studies characterizing optimal dosing parameters (eg, frequency and inter-dose interval). The following case describes the effects of two ketamine administration regimens in a patient with a 15-year history of depression.

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Ketamine as a Novel Antidepressant: From Synapse to Behavior
Author(s): James W. Murrough, M.D.
Recent reports of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, even in treatment-resistant populations, has spurred translational therapeutic and neuroscience research aimed at elucidating ketamine’s mechanism of action. This article provides a concise overview of research findings that pertain to the effects of low-dose ketamine at the cellular, neurocircuitry and behavioral levels and describes an integrated model of the action of ketamine in depression.

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Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
Author(s): James W. Murrough, M.D., Dan V. Iosifescu, M.D., Lee C. Chang, M.D., Rayan K. Al Jurdi, M.D., Charles M. Green, Ph.D., Andrew M. Perez, M.D., Syed Iqbal, M.D., Sarah Pillemer, B.A., Alexandra Foulkes, M.S., Asim Shah, M.D., Dennis S. Charney, M.D., and Sanjay J. Mathew, M.D.
Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.

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Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Author(s): Duman RS, Aghajanian GK.
Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.

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