The morbidity and mortality of depression are staggeringly clear. Yet, other than atypical antipsychotic augmentation and transcranial magnetic stimulation programs, little novel research has been proposed to develop successful treatments (1). Ketamine is an anesthetic medication with rapid antidepressant effects that are robust, rapid, and nonsustained (2). There has been recent interest in large-scale drug development of ketamine. While debate continues on the therapeutic mechanism of action and potential liability (3), early clinical data have been impressive and have supported development of large-scale, well-designed programs of intranasal esketamine, the S(+) enantiomer of ketamine, for treatment-resistant depression and major depression with suicidality. While ketamine and esketamine are available in highly regulated clinical trials, the use of ketamine for treatment of depression and chronic pain in clinical practice, in various delivery models, is increasing. The case presented here illustrates the potential unintended consequences and risks of ketamine prescribed for depression before optimal dosing, routes of administration, and specific indications have been established.
Pharmacologically, ketamine is a derivative of phencyclidine, and in addition to its primary mechanism of N-methyl-d-aspartate receptor antagonism, it may also increase levels of dopamine, norepinephrine, and serotonin in the brain (4). While likely multifactorial, ketamine’s dopaminergic effects may promote euphoria and contribute to risk of dependence via the dopamine reward pathway (5, 6). The abuse potential of different formulations has not been determined. However, the pharmacokinetic properties of intranasal drug delivery, including rapid onset of action and improved bioavailability, may increase its abuse potential (7).
Ketamine’s established availability as an anesthetic presents a dilemma for prescribers who otherwise would not have prescription access to an investigational medication for depression. Many argue that the only current recommendation is simply not to prescribe ketamine, given a lack of clinical evidence. Others believe that ketamine’s robust antidepressant effects warrant immediate prescribing for treatment of depression. Current unregulated practice and lack of phase III clinical trial data challenge each recommendation.
An Internet search with the words “ketamine and pharmacy” yields multiple web sites through which patients may contact prospective ketamine prescribers and pharmacies. Mr. A’s access to ketamine and experience with his ketamine prescriber was not unique. He received monthly ketamine shipments, across state boundaries, of intranasal and sublingual formulations prescribed for multiple doses each day, with infrequent medication management appointments or telephone calls with his prescriber.
It is impossible to know the number of patients who receive prescriptions for ketamine for depression outside of research settings. Given the types of ketamine formulations that are typically dispensed in the community, including intranasal formulations, it is likely that most prescriptions are sold from compounding pharmacies. Traditional retail pharmacies are not able to manipulate the dosage form or access the raw ketamine compounding powder, but compounding pharmacies have the infrastructure to create ketamine formulations. The role of compounding pharmacies and ketamine was highlighted in a recent report in which a patient obtained intranasal ketamine after being referred to a neurologist for ketamine based on her history of migraines and to treat her severe depression (8).
The Internet provides today’s patients easy access to early research data on ketamine’s antidepressant effects. Although there are positive aspects of patients being informed, this access may amplify the pressure or arguable ethical dilemma some prescribers may feel when patients request cutting-edge treatments. This is particularly challenging for patients like Mr. A, who have experienced varying degrees of depression and then experience a treatment like ketamine with an immediate, robust antidepressant effect.
Although the treatment team’s position is not to recommend off-label use of ketamine for maintenance treatment of depression, the team did not interfere with Mr. A’s receiving ketamine until there were concerns about misuse and dependence. Mr. A expressed frustration that the treatment team did not understand that ketamine was the only prescribed substance that had ever treated his depression.
Mr. A’s use of alcohol became more apparent later in the course of his treatment. Underreporting of alcohol use (9) and co-occurrence of alcohol use and depression (10) are both common and consistent with the literature. However, Mr. A’s lack of interest in addiction treatment made the dual diagnosis treatment challenging (11). Additionally, individuals with dual diagnoses are more likely to die by accidents compared with those with a single diagnosis (12). Mr. A was unwilling to consider changes in his antidepressant regimen or initiate dependence treatment, particularly when recommendations included ending his ketamine prescription. Patients in this situation may perceive that a practitioner who does not prescribe ketamine for treatment of depression simply does not understand the extent of their suffering, and thereby is withholding treatment.
Prescribing ketamine for depression is currently off label, which is defined as prescribing for an indication, dosage, or dosage form that has not been approved by the Food and Drug Administration (FDA) (13). Off-label drug use is common in psychiatry; however, a clear monitoring plan should be in place to avoid or manage serious adverse events. In this particular case, minimal monitoring occurred as Mr. A received monthly supplies of ketamine without being seen for follow-up.
If esketamine, a schedule III controlled substance, does attain FDA approval for treatment of depression, we hope this case report will promote discussion for monitoring ketamine use. Ketamine dependence has been reported in the literature with descriptions of tolerance, but not with withdrawal (14). This was the case with Mr. A, as he had symptoms of tolerance without any specific, apparent withdrawal symptoms. Knowing the warning signs of ketamine dependence is important, especially if ketamine becomes a mainstream treatment method. Given the potential for misuse and addiction, close follow-up and monitoring of ketamine prescribing will be essential.
This case report should encourage ongoing dialogue about ketamine prescribing in non-research settings. Outside of registered clinical trials, ketamine is currently being prescribed for depression treatment with no mechanism to report outcomes, either positive or negative (15). At what point does prescribing a schedule III medication with addictive potential, in a manner that lacks clear dosing parameters, lead to more harm than benefit? This case illustrates the potential harm of current, off-label, poorly regulated ketamine prescribing. Additionally, Mr. A’s history of alcohol misuse with a remote history of alcohol addiction treatment may have made him a less than ideal candidate for ketamine. Without additional research and safety data, patients with a history of substance use may not be good candidates for ketamine therapy. Continued scientific, registered, clinical investigation regarding the use of ketamine and esketamine for treatment of depression and suicidality will be critical for drug development.
References
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Li X, Frye MA, Shelton RC: Review of pharmacological treatment in mood disorders and future directions for drug development. Neuropsychopharmacology 2012; 37:77–101
Newport DJ, Carpenter LL, McDonald WM, et al: Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172:950–966
Sanacora G, Schatzberg AF: Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology 2015; 40:1307
Lindefors N, Barati S, O’Connor WT: Differential effects of single and repeated ketamine administration on dopamine, serotonin, and GABA transmission in rat medial prefrontal cortex. Brain Res 1997; 759:205–212
Stockwell T, Donath S, Cooper-Stanbury M, et al: Under-reporting of alcohol consumption in household surveys: a comparison of quantity-frequency, graduated-frequency, and recent recall. Addiction 2004; 99:1024–1033
Kessler RC, Crum RM, Warner LA, et al: Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry 1997; 54:313–321
Pettinati HM, Oslin DW, Kampman KM, et al: A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry 2010; 167:668–675
Dickey B, Dembling B, Azeni H, et al: Externally caused deaths for adults with substance use and mental disorders. J Behav Health Serv Res 2004; 31:75–85
Dr. Frye has been a consultant (unpaid) for Allergan, Merck, Myriad, Sanofi-Aventis, Sunovion, Supernus Pharmaceuticals, Takeda Global Research, Teva Pharmaceuticals, and United Biosource Corporation; has received grant support from Myriad, Pfizer, NARSAD, NIMH, the National Institute of Alcohol Abuse and Alcoholism, and the Mayo Foundation; and has received travel support from the Chilean Society of Neurology, Psychiatry, and Neurosurgery, Advanced Health Media, GlaxoSmithKline, the Colombian Society of Neuropsychopharmacology, AstraZeneca, Bristol-Myers Squibb, Otsuka, and Sanofi-Aventis. The other authors report no financial relationships with commercial interests.
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