Ketamine: Magic Bullet?
In the news: Recent publication of the almost immediate resolution of treatment-resistant depression (TRD) following Ketamine infusion has sparked tremendous interest within the fields of clinical psychiatry and psychotropic drug development. It has also sparked the entrepreneurial development of specialized ketamine clinics, despite the lack of Federal Drug Administration (FDA) approval of ketamine for this purpose. And, of course, third-party payers are being asked to cover these services.
Should they? After all, there is replicated evidence for ketamine’s rapid antidepressant effects.[i]
Background: Ketamine was FDA-approved as an anesthetic agent in 1964 and was widely used for soldiers injured in the Vietnam War.[ii] Its legitimate role has expanded over the years to include pain management and veterinary surgery. Ketamine was also found to cause neurocognitive symptoms (dissociation, altered perception, increased suspiciousness, hostility, decreased verbal fluency, impaired memory),[iii] producing a pharmacologic model of schizophrenia.
The appeal: Depression is common, recurrent, disabling, painful, and sometimes life-threatening. It is frequently comorbid with many other medical conditions that are adversely affected (e.g., diabetes, heart disease) by depression. All current antidepressants take weeks to months to work. Effective therapies (e.g., cognitive behavioral therapy [CBT] and interpersonal therapy [ITP]) also take several weeks to see improvement. Less evidence-based therapies (e.g., psychodynamic therapy) take months to years. Only stimulants (dextro-amphetamine, methylphenidate, and others) – used off-label – work rapidly for some to mitigate certain symptoms (e.g., poor energy, lack of appetite or interest). Electroconvulsive therapy (ECT) is currently the gold standard for TRD, and even that is not immediate. It would be terrific to give sudden, complete and sustained relief to those suffering from TRD. The global public health benefit would be immense.
The downside: The psychosis-like symptoms described above were probably also instrumental in ketamine’s growing recreational use (aka: K, ket, Special K). Frequent repetitive use is associated with ulcerative cystitis, memory deficits, impaired neurocognitive function and addiction.
Potential benefits: Acknowledging the need for further studies, the benefits of compassionate use in the hospice setting may outweigh the risks.[iv] It is palliation to relieve the suffering of depression in the terminally ill. There is also evidence for decreased suicidality in TRD treated with ketamine.[v]
The real benefit: The rapid antidepressant effect of ketamine is most significant for its heuristic value in the development of new antidepressants. Human and animal studies on ketamine’s effect in the brain have identified new neurotransmitter systems (e.g., glutamate), certain receptor types (NMDA and AMPA)[vi] and specific brain regions (e.g., the infralimbic prefrontal cortex [IL-PFC])[vii] as targets for future antidepressant drug action. This research lays the groundwork for the development of safer, rapid-acting, novel agents to change the course of treatment-resistant depression.
In the meantime, use of ketamine infusion for TRD should be decided on an individual case basis, and it should be restricted to the most extreme cases, e.g., the terminally ill or the seriously suicidal.
[i] Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of N-methyl-D-aspartate antagonist in treaqtment-resistant major depression. Arch Gen Psychiatry 2006; 63:856-64.
[ii] Morgan CJA, Curran HV. Ketamine use: a review. Addiction 2011; 107:27-38.
[iii] Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry 1994; 51:199-214.
[iv] Iglewicz A, Morrison K, Nelesen RA, et al. Ketamine for the treatment of depression in patients receiving hospice care: a retrospective medical record review of thirty-one cases. Psychosomatics 2015; 56:329-37.
[v] Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66: 522-6.
[vi] Machado-Vieira R, Salvadore G, DiazGranados N, Zarate CA. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009; 123: 143-50.
[vii] Fuchikami M, Thomas A, Wohleb ES, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. PNAS 2015; 112:8106-11.