Efficacy, Safety of Long-Term Ketamine Administration Still In Question

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Ketamine, originally approved by the FDA in 1970 as an anesthetic, is increasingly being recognized as an option in treatment-resistant depression.
Ketamine, originally approved by the FDA in 1970 as an anesthetic, is increasingly being recognized as an option in treatment-resistant depression.

Ketamine, originally approved by the US Food and Drug Administration (FDA) in 1970 as an anesthetic, is increasingly being recognized as an option in treatment-resistant depression. Recent reports of successful trials of ketamine for depression and suicidality have resulted in the establishment of numerous ketamine clinics throughout the United States.1 However, questions remain regarding ketamine's safety and efficacy, particularly with repeated administration.2

The burgeoning interest in ketamine has been fueled in part by the shortcomings of standard pharmacotherapies currently approved for the treatment of depression. Conventional antidepressants primarily exert their effects through modulation of monoaminergic neurotransmitters such as serotonin, norepinephrine, and dopamine.3 Despite the availability of several classes of antidepressants, up to one-third of patients with major depressive disorder (MDD) have treatment-resistant depression, characterized by absent or incomplete responses to pharmacologic treatment despite adequate dosing, duration, and adherence.4 Due to problems of definition and a paucity of data,5 the prevalence of treatment-resistant depression in patients with bipolar disorder is harder to pinpoint, yet current therapeutic strategies are clearly inadequate. In a prospective investigation of the weekly symptomatic status of patients with bipolar disorder, patients with bipolar I and bipolar II reported that they experienced depressive symptoms in 31.9% and 50.3% total weeks, respectively.6,7

Antidepressant agents typically have a delayed onset of action, often requiring weeks to months of daily administration before their clinical effects are fully exerted.8 Unlike conventional antidepressants, ketamine does not target the monoaminergic system; its mechanism of action is presumed to involve the blockade of glutamatergic N-methyl-D-aspartate (NMDA) receptors.3 Ketamine typically induces remission of depression within 2 to 24 hours of a single, slow, intravenous infusion, albeit for a limited duration of time.9,10 Results are typically sustained for up to a week after administration.11 In a review published in Harvard Review of Psychiatry,  Ioline D. Henter, MA, and colleagues from the National Institute of Mental Health wrote, “No other treatment for depression to date has shown similar effects with regard to the magnitude of response to a single dose for treatment-resistant patients.”9

An expert consensus statement by The American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments published in 2017 by JAMA Psychiatry recommends that the risks and benefits of ketamine treatment be carefully assessed in each patient based on the severity of their depression, duration of the current episode, treatment history, and treatment urgency. The statement lists recommended components of a pre-treatment evaluation process to assess the appropriateness of ketamine treatment, including a comprehensive diagnostic assessment, assessment of baseline symptoms in order to track changes with treatment, evaluation of risk factors, a careful medication history, and an informed consent process. The statement offers further recommendations on treatment setting, clinician training, medication delivery, and safety measures.12

While single-dose ketamine infusions appear to have an acceptable safety profile, based in part on the agent's 50-year history of use as an anesthetic, the safety and efficacy of repeated infusions in the context of depression treatment are yet to be established. A recent clinical trial in 77 patients with unipolar depression and 20 with bipolar depression evaluated the efficacy and tolerability of 6 ketamine infusions administered over the course of 12 days.13 At 24 hours following the first infusion, the response rate was 14.4%; 24 hours following the 6th infusion, the response rate was 68.0%. Remission followed a similar trajectory, with a rate of 9.3% following the first infusion and 50.5% following the 6th. Treatments were of acceptable tolerability.

Another recent small observational retrospective chart review described the use of maintenance ketamine infusions exceeding an initial series of up to 8 infusions in 11 patients with severe treatment-resistant depression.14 All patients demonstrated improvements in Beck Depression Inventory II (BDI-II) score following a course of acute treatment with 6 or 8 infusions and scores lower than baseline during maintenance treatment and at its conclusion. No clinically significant adverse effects were reported. The researchers described the study as “the largest cohort of patients to receive ketamine treatments on an ongoing basis for depression,” underscoring the present lack of data on prolonged ketamine use. “No one knows how much is too much or how frequent is too frequent,” Samuel Wilkinson, MD, assistant director of Yale Depression Research Program in New Haven, Connecticut, told Psychiatry Advisor. Dr Wilkinson noted that the drug has a “non-trivial potential for abuse” and is frequently used for recreational purposes in the United Kingdom and Southeast Asia. “To what extent offering ketamine as a therapy may potentially increase rates of abuse in the United States is not known.”

Dr Wilkinson also noted that the extended recreational use of ketamine has been associated with delusions, negative effects on cognition, and bladder toxicities, leading to a need for psychiatrists to be cautious about using it as a long-term treatment. “One area of interest is the question about how to keep people well without continued use of the drug,” he stated.

References

  1. Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017;174(7):695-696.
  2. Loo C. Is ketamine ready to be used clinically for the treatment of depression?The Medical Journal of Australia. 2015;203(11):425.
  3. Strasburger SE, Bhimani PM, Kaabe JH, et al. What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities.J Clin Pharm Ther. 2017;42(2):147-154.
  4. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17(2):111-126.
  5. Pacchiarotti I, Mazzarini L, Colom F, et al. Treatment-resistant bipolar depression: towards a new definition. Acta Psychiatr Scand. 2009;120(6):429-440.
  6. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder.JAMA Psychiatry. 2002;59(6):530-537.
  7. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.JAMA Psychiatry. 2003;60(3):261-269.
  8. Machado-Vieira R, Baumann J, Wheeler-Castillo C, et al. The timing of antidepressant effects: a comparison of diverse pharmacological and somatic treatments.Pharmaceuticals (Basel). 2010;3(1):19-41.
  9. Henter ID, de Sousa RT, Zarate CAJ. Glutamatergic modulators in depression.Harvard Review of Psychiatry. 2018 ;26(6):307-319.
  10. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression.Am J Psychiatry. 2016;173(8):816-826.
  11. Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459-1472.
  12. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders.JAMA Psychiatry. 2017;74(4):399-405.
  13. Zheng W, Zhou Y-L, Liu W-J, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression.J Psychiatr Res. 2018;106:61-68.
  14. Archer S, Chrenek C, Swainson J. Maintenance ketamine therapy for treatment-resistant depression.J Clin Psychopharmacol. 2018;38(4):380-384.
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