An explosion of research on ketamine and its 2 isomers, esketamine and arketamine, ensued. A search on PubMed (April 12, 2019; https://www.ncbi.nlm.nih.gov/pubmed) listed 4669 articles published with the search word “ketamine” in the past 5 years. Although ketamine has been FDA approved as an anesthetic since 1970, its use in depression has been off label, greatly limiting its access to most depressed individuals. Ketamine remains off label for the treatment of TRD but is administered throughout the US by physicians of various specialties in ketamine clinics, where it is usually administered intravenously, and with no consistent protocol.
Long-term studies are lacking to quantify duration of treatment, frequency of treatment, dosing, and long-term safety. A recent publication did monitor long-term tolerability in 14 patients who received from 12 to 45 IV ketamine infusions over a period of 14 to 126 weeks with no significant long-term serious side effects reported.2
Esketamine’s story: chirality and stereoisomerism
All proteins, enzymes, and receptors are constructed of a core sequence of amino acids. As life evolved on our planet, a random choice was made whenever an amino acid had at least one carbon atom with 4 unrelated groups attached—resulting in a subset of amino acids having mirror image structures, one found in living systems and the other absent. This results in the phenomena of chirality, whereby when you look at the attached groups on the carbon atom, the smallest to largest groups rotate either clockwise or counterclockwise.
Many drugs, when synthesized, contain a 50:50 mixture of these chiral compounds, and some drugs can have numerous chiral carbon sites. Depending on the arrangement of these 4 attached groups on the carbon atom, the drug is classified as either “es” or “S” for left rotating, or “ar” or “R” for right rotating. The common analogy used is “handedness.” Although the left hand and right hand look identical at first glance, they are not superimposable. Rather, they are mirror images of each other. If you had a lock that required your hand’s 3-dimensional structure to open it, only one hand would work. These basic chemical principles create the phenomena of stereoisomerism, and in most cases the “es” or the “ar” isomer of a drug binds much tighter and cleaner to its associated receptor.
Ketamine is a racemic mixture, so when it is synthesized it contains 50% esketamine and 50% arketamine. It is well established that esketamine binds approximately 4 times tighter to the NMDA-glutamate receptor than arketamine. However, both molecules have relevant and significant effects on receptors in the human brain. Each isomer is metabolized by liver enzymes, and some of the metabolites retain chirality, while others do not. An evolving research literature continues to expand our understanding of the differences between these 2 isomers, but much remains to be learned.
Janssen, the manufacturer of Spravato, chose to develop its intranasal spray with the isomer esketamine. Initial dosing studies determined the IV doses of esketamine required to achieve similar rapid onset efficacy in TRD patients to that of IV ketamine. Once these serum concentrations were established for esketamine, Janssen developed an intranasal spray delivery system to achieve these same concentrations to allow for intranasal administration. At the time of FDA approval of Spravato, Janssen had studied it for 9 years, and in over 1700 patients with TRD.
Dr Miller reports that he is on Janssen’s Advisory Board and on the Speaker’s Bureau for Spravato.
1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
2. Wilkinson ST, Katz RB, Toprak M, et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry. 2018;79:pii:17m11731.
3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215.
4. Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry. 2019; 76:337-338.
5. Marton T, Barnes DE, Wallace A, et al. Concurrent use of buprenorphine, methadone, or naltrexone does not inhibit ketamine’s antidepressant activity. Biol Psychiatry. March 26, 2019; Epub ahead of print. ❒