Ketamine for depression - Knowns, unknowns, possibilities, barriers, and opportunities

The author of this JAMA Psychiatry opinion piece writes: "Many drugs used in medicine have on- and off-label indications that span different medical disciplines. Ketamine now has evidence of efficacy for emergency and nonemergency sedation, acute and chronic pain, and depression. For some of these indications, ketamine has been used in both children and adults. Ketamine is also being experimentally investigated, with or without assisted psychotherapy, for other neuropsychiatric indications, including anxiety, alcohol and substance use disorders, and posttraumatic stress disorder. Major depressive disorder (MDD) is associated with distress, suicide risk, impaired quality of life, disability-adjusted life-years lost, medical comorbidities, and early mortality risk. With this background, given the well-established rapid antidepressant benefits of racemic ketamine, it surprising that racemic ketamine is struggling for integration into mainstream psychiatry. In the US, intravenous ketamine for depression is off label and is not covered by most insurance companies. Intranasal esketamine was approved by the US Food and Drug Administration in 2019 but it is expensive and is unavailable or unaffordable in developing countries … There are regulatory hurdles associated with the approval of ketamine for any indication other than anesthesia. For example, who will fund the expensive randomized clinical trials (RCTs) for a drug that is out of patent and from which no profit can be made? To help the reader understand this, an oral ketamine session for depression can be conducted in a public hospital in India at a cost of about half a US dollar. An approval for orally administered generic racemic ketamine for contexts in depression could inexpensively improve the management of depression in developing countries with limited health care infrastructure and resources, where payments are most commonly made directly by patients rather than by insurers. In this regard, ketamine is on the World Health Organization’s list of essential drugs, but only as an injection for anesthesia, and would require approval to be mixed with water for use in oral administration for depression.  Orally administered ketamine presents an opportunity. Oral ketamine sessions are easy to conduct6 with low, spaced doses dispensed in small quantities for short durations, the risk of drug diversion and misuse may be reduced. The oral bioavailability of ketamine is about 20% to 30%, but low oral bioavailability does not preclude the prescription of many other drugs, such as ramelteon, lurasidone, and propranolol. A small uncontrolled, open-label investigation of 30 patients with depression found that a fixed oral dose of 150 mg of racemic ketamine has modest therapeutic efficacy and that higher doses are well tolerated; the slower absorption when a solution of ketamine is sipped across 10 to 15 minutes obviates clinical risks. Independent investigators in developing countries can conduct the country-specific RCTs to assess efficacy and safety of oral ketamine, which is necessary to obtain local regulatory approvals for oral ketamine for MDD. Such RCTs need to be free of bias. In summary, ketamine has the potential to change our approach to the clinical management of depression if knowledge, attitudinal, and regulatory barriers can be overcome, and if risks related to comorbidities and concurrent medications are addressed by close supervision."

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