Continuing Education
  • Ketamine and Treatment-Resistant Depression

    Major depressive disorder affects tens of millions of people each year. One-third of those affected have depression that is resistant to conventional pharmacologic, psychologic, or somatic treatments. Patients with treatment-resistant depression have few remedies other than electroconvulsive therapy or transcranial magnetic stimulation. Recent research has highlighted the promising antidepressant effects of subanesthetic ketamine infusions. This journal course examines the efficacy of ketamine for treatment-resistant depression. Evidence from 10 systematic reviews and randomized controlled trials suggest that most of the researchers concluded ketamine significantly decreased depression severity ratings at short-term assessment intervals, whereas evidence examining the long-term effects is lacking. Ketamine infusion therapy was generally well tolerated, with minimal untoward effects. Large, randomized controlled trials are needed to discern the longer-term efficacy, tolerance, and dependence profiles of ketamine infusions. Optimal dosing schedules to best prolong the antidepressant effects of ketamine have yet to be determined.

    Keywords: Ketamine, MADRS, major depressive disorder, refractory depression, treatment-resistant depression.

    The AANA Journal Course is published in each issue of the AANA Journal. Each article includes objectives for the reader and sources for additional reading. A 5-question open-book exam for each course is published on CRNA Knowledge Network and will remain live on the site for a period of 3 years. One continuing education (CE) credit can be earned by successfully completing the examination and evaluation. Each exam is priced at $35 for members and $21 for students but can be taken at no cost by using one of the six free CEs available annually to AANA members as a benefit of membership. This educational activity is being presented with the understanding that any conflict of interest has been reported by the author(s). Also, there is no mention of off-label use for drugs or products.

    Objective

    Upon completion of this course, the reader will be able to:

    1. Discuss the role of ketamine in alleviating treatment-resistant depression.

    Introduction

    Major depressive disorder (MDD) affects approximately 13 to 16 million people in the United States annually.1,2 Individuals with MDD experience persistent feelings of sadness, loss, anger, and disinterest.3 These feelings affect physical health as well as affecting thinking and behavior.3 Depressive disorders have a wide range of classifications, categories, and attributes.3 The primary problem is that 5 to 6 million patients with MDD are resistant to conventional pharmacologic, psychologic, or somatic treatments.4 This clinical condition is called treatment-resistant depression (TRD).1

    Individuals with TRD are at increased risk of alcoholism, drug abuse, hospitalizations, and suicide.2,3 Two alternative treatments reserved for patients with TRD are electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).4 Although either remedy may prove effective, relief from depression or suicidal ideation may not occur for 2 to 6 weeks.1,2,4 Few treatment options remain for patients with TRD who have failed to respond to ECT or TMS.1,2,4 New therapies for MDD/TRD must bridge the therapeutic gap that exists between current pharmacotherapy regimens. Subanesthetic ketamine infusions may be a safe and effective therapy for TRD.2,5

    Epidemiology and Treatment of Treatment-Resistant Depression

    The risk of MDD occurring during a lifetime is approximately 15%.6 The prevalence rates for males are half the rates for females.6 Major depressive disorder is most often diagnosed in women between the ages of 25 and 44 years.3 Those with severe MDD suffer restlessness, agitation, flattened affect, and body weight fluctuations.3 Up to two-thirds of individuals with depression do not recognize the symptoms of depressive disorder in themselves and seldom seek professional consultation.3 Conventional therapies for MDD include pharmacotherapy, psychotherapy, and other somatic remedies.1-3

    Current antidepressant pharmacotherapy regimens include monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and selective norepinephrine reuptake inhibitors.6 Medication regimens are often prescribed concurrently with counseling or psychotherapy.3 Multimodal therapy relieves the symptoms of depression for many patients.3 Researchers estimate that 70% to 80% of individuals can attain a substantial decline in symptoms when they are compliant with appropriate treatment.3 Unfortunately, patients may be noncompliant with pharmacotherapy regimens because of side effects such as dry mouth, insomnia, dizziness, weight gain, cardiac dysrhythmias, hypertension, decreased libido, and suicidal ideation (Table 1).1,2 Additionally, achievement of therapeutic blood levels for conventional antidepressants may take 3 to 8 weeks.1,2,6

    The causative and clinical correlational factors of TRD include neurotransmitter dysfunction, history of trauma, neurotransmitter polymorphisms, and social interaction disorders.3 Current pharmacologic treatments of MDD enhance transmission in the serotonergic or noradrenergic neurotransmitter systems.6 Patients may be noncompliant with their pharmacologic regimens because of the aforementioned adverse side effects.1,2 Up to 30% of patients with MDD do not respond adequately to standard therapy regimens.6 Consequently, researchers seek a greater understanding of the etiology of MDD and novel treatment strategies.6 Neuromodulative therapeutic techniques, such as ECT and TMS, are an option for patients with TRD.1

    Electroconvulsive therapy is considered by some to be very effective in treating TRD.1,4,5 Induced seizures and generalized cortical postictal electroencephalographic suppression are thought to be responsible for the beneficial antidepressant effects, which appear within 7 days of treatment.1,5 Electroconvulsive therapy relieves symptoms of depression for 60% of patients with TRD.1,5 However, this remedy is associated with persistent, negative cognitive side effects such as memory loss as well as with severe social stigma.1,5 Another consideration is that patients receiving ECT must undergo general anesthesia.1

    Those patients unwilling or unable to undergo a general anesthetic may benefit from noninvasive TMS, which does not require anesthesia.1 Electrical currents generated by a magnetic coil placed on the scalp modulate neural activity by producing changes in cortical excitability.1,4 Transient headaches, discomfort, insomnia, and unpleasant phantosmia are the most commonly reported side effects of TMS therapy.1 Because of the limited study of TMS therapy in TRD, information about its long-term efficacy is lacking.1 Further limiting the use of TMS is the small number of facilities equipped to provide this therapy.1,4 Therefore, additional treatment options for TRD, such as ketamine infusion therapy, should be investigated for the benefit of patients who are unwilling or unable to undergo or are unresponsive to the neuromodulatory techniques of ECT and TMS.2

    Possible Mechanism of Action of Ketamine in Treating Treatment-Resistant Depression

    In 2017, Ionescu and Papakostas2 hypothesized that ketamine manipulates the glutamatergic system and the release of brain-derived neurotrophic factor. Improved mood as a result of elevated levels of brain-derived neurotrophic factor may provide some relief from depressive symptoms (Figure 1).7 In contrast to TMS therapy, ketamine is widely available, and its use does not require providers trained and equipped to use specialized devices such as with ECT and TMS.5

    Evidence Examining Ketamine in Treating Treatment-Resistant Depression

    Providers should be familiar with the evidence examining the use of ketamine in the treatment of TRD. A systematic search and appraisal of the quality of evidence pertaining to a problem helps decrease bias.8,9 The following is based on a systematic search of randomized controlled trials and systematic reviews (2007-2017) examining the use of ketamine in humans as a therapy for TRD. The search initially revealed 11 evidence sources meeting the inclusion criteria.10-20 Closer examination revealed that one of those sources16 included all of the studies reviewed by Wan et al,14 and it is therefore excluded from Table 2. See Figure 2 and Table 2 for a description of the search and a summary of the evidence, respectively. All but 214,17 of the sources were systematic reviews.

    All sources compared the efficacy of ketamine therapy for the treatment of depressive symptoms in MDD/TRD.10-20 The studies included adults with current diagnoses of TRD and MDD (including bipolar and unipolar). Exclusion criteria included serious comorbidities, postpartum depression, substance abuse/dependence, psychosis/psychotic disorders, recreational use of ketamine or phencyclidine, or serious suicidal/homicidal ideation.10-20 Trials involving ketamine administration in the context of surgery or ECT were specifically excluded by Lee et al12 and Xu et al.18 Caddy et al10 specifically included ECT data. There were no significant age or gender differences between the control and intervention groups within studies. For all sources, adequate blinding was difficult because of the temporary dissociative and psychotomimetic effects of ketamine, which appear shortly after administration.10-20

    Investigators used a variety of administration protocols. The most common was a single infusion of ketamine, 0.5 mg/kg, administered over 40 minutes. Nine groups of investigators10-16,19,20 used this protocol. Six sources10,12,13,15,18,19 included results from ketamine infusions at lower dosages and different infusion rates (0.1-0.4 mg/kg over 40 minutes or a 0.27 mg/kg infusion over 10 minutes followed by 0.27 mg/kg over 20 minutes). Multiple-infusion protocols were used by 9 sources.10-13,16-20 Additionally, 4 sources13,16,18,19 administered 50 mg of ketamine via intranasal atomization. Xu et al18 placed no restrictions on the method of ketamine administration included in the study. Coyle and Laws11 and Papadimitropoulou et al20 did not explain the ketamine infusion regimens included in the studies. The most common comparator was saline placebo.10-13,15-19 Active placebo or pseudoplacebo was used in 5 sources.12-15,20

    Four sources discussed a washout period of 1 to 4 weeks for all psychotropic medications before beginning experimental treatment.13-15,18 Four sources12,13,17,18 did not place restrictions on the continuation of current psychotropic medications during the trials. Kishimoto et al15 stated that patients’ current antidepressant and antipsychotic medications continued for the duration of the trial.

    It was unclear whether the participants were treated as hospital outpatients or in outpatient centers in the majority of sources.10-14,16,18-20 Singh et al17 specified that participants were treated as outpatients for the duration of the trial. Kishimoto et al15 cited trials treating participants as both outpatients and inpatients.

    Sources measured the primary outcome as a 50% or greater decrease in the severity of depressive symptoms as measured by scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) or the Hamilton Depression Scale (HAM-D).10-20 These instruments measure clinically significant affective, cognitive, somatic, and behavioral symptoms of depression and response to treatment over time.21-23 The 10-item MADRS assesses perceived sadness, sleep abnormalities, appetite fluctuations, concentration difficulties, pessimistic thoughts, and suicidal ideation.21-23 Items on the HAM-D scale include depressed mood, suicidal ideation, somatic complaints, gastrointestinal symptoms, and loss of interest.23 The investigators obtained baseline depression severity ratings from all participants before the intervention and again at specific timepoints after the intervention.10-23 Assessment scores at 24 hours after the intervention were the main outcome parameter.10-16,18,19 Papadimitropoulou et al20 and Singh et al17 recorded postintervention depression severity rating scores at 14 days and 15 days, respectively, rather than 24 hours.

    Dose, Improvement, Untoward Effects

    Overall, the authors of the sources reviewed concluded that ketamine was efficacious in treating TRD.10-20

    Dose. Most of the researchers observed that a single dose of intravenous ketamine, 0.5 mg/kg infused over 40 minutes, significantly decreased depression severity rating scores at 24 hours compared with baseline assessments.10-20 Most sources reported rapid and robust antidepressant effects first apparent within 40 minutes15 to 4 hours18 of a single ketamine infusion. Table 3 summarizes common dosing regimens.

    Short-term Improvement. Authors10-16,18,19 reported significant decreases in depression severity scores at 24 hours after infusion. Compared with saline placebo and active placebo effects, Kraus et al19 reported an average reduction of 10.9 points on the HAM-D and 20.8 points on the MADRS when measured 24 hours after ketamine infusion and compared with baseline scores. Wan et al14 discussed similar results, finding the mean reduction (SD) in MADRS scores at 24 hours after ketamine infusion to be 19 (11.7) points. McGirr et al13 concurred, reporting a standardized mean difference (SMD) of 0.90 (95% CI, 0.66 to 1.13; P ≤ .001) in favor of ketamine for a reduction in depression severity scores at 24 hours. Caddy et al10 reported a statistically significant reduction in scores at 24 hours favoring ketamine over placebo (SMD, −1.42, 95% CI −2.26 to 0.57; P = .001) and over the active placebo midazolam (SMD, 7.95, 95% CI, −12.67 to −3.23; P = .001). Lee et al12 and Xu et al18 reported similar findings. Compared with placebo, ketamine significantly decreased depression severity scores at 24 hours (SMD, 1.01, 95% CI, 0.69 to 1.34; P < .00112 and SMD, −1.4, 95% CI, −2.0 to −0.9).18 Kishimoto et al15 also found in favor of ketamine over placebo or pseudoplacebo in reducing depressive symptoms and severity at 24 hours (Hedges g = −1.00, 95% CI, −1.28 to −0.73; P < .001).

    Long-term Improvement. Only 2 sources17,20 examined the long-term efficacy of ketamine to reduce depression severity scores from baseline to days 14 and 15 after treatment. Papadimitropoulou et al20 found that ketamine significantly reduced depression severity scores at day 14 (SMD, −14.0, 95% CI, −19.9 to −8.0; no P value reported) compared with placebo.

    Singh et al17 compared a twice-weekly and thrice-weekly 0.5 mg/kg ketamine infusion schedule vs placebo for reduction in depression scores from baseline to day 15. At day 15, depression scale scores for the twice-weekly dosing group declined by a mean (SD) of −18.4 points (12.0; P < .001) compared with placebo’s mean reduction of −5.7 points (10.2; P < .001). At day 15, depression scale scores for the thrice-weekly dosing group declined by a mean (SD) of −17.7 points (7.3; P < .001) compared with placebo’s mean reduction of −3.1 points (5.7; P < .001).17

    Untoward Effects. Mild side effects such as headache, dizziness, nausea, transient increases in heart rate and/or blood pressure, transient dissociative effects, and transient psychotomimetic effects were reported by 10 groups of researchers.10-19 Wan et al14 described a discretional study protocol using the short-acting ß-blocker labetalol to treat transient increases in blood pressure (up to 180/100 mm Hg) or heart rate (up to 110/min). If the hemodynamic variations were treated, yet still outside of the study parameters after 3 consecutive measurements, the ketamine infusion was discontinued.14 Ten sources10-19 reported the occurrence of mild psychotomimetic and dissociative effects, which resolved between 60 and 240 minutes after administration. In some instances, serial infusions were reported to attenuate this response.12,14,16,18 No participant displayed severe psychotic symptoms, and few serious adverse events occurred.10-20 The sources concluded that the adverse events were unrelated to ketamine administration.11,17-18 One participant experienced extreme anxiety related to stressful life events and withdrew from the study.17 One participant experienced affective switch.11 Two participants attempted suicide.17-18 One suicide attempt occurred during the washout period before the study.18 The second suicide attempt occurred on day 40 of the study, 28 days after the participant’s last ketamine infusion.17 One group did not report the occurrence of any side effects.20 No deaths related to ketamine infusions were reported.10-20

    The reported range of time to resolution of side effects and acute behavioral changes was between 1 and 4 hours after completion of the ketamine infusion.12,14,18,19 Attrition rates throughout the sources shared similar causes, such as marked positive responses to ketamine,13,15 lack of efficacy (from the placebo group),17 anxiety/palpitations,14,17 and extreme vasovagal response to venipuncture requiring inpatient observation.14,19 Some sources did not report all-cause attrition data.11,12,18,20

    Limitations of the Evidence Examining Ketamine in Treating Treatment-Resistant Depression

    The major limitations described by most sources were short study durations and small numbers of participants.10-14,17-18 Adequate descriptions of blinding, sequence generation, and allocation concealment were lacking in the work of Lee at al12 and McGirr et al.13 There was a risk of functional unblinding in any study that did not incorporate an active control because psychotomimetic and dissociative side effects caused by ketamine administration would be noticed by study participants and observers.10,11,13,15,17 However, this was deemed inevitable and labeled as low risk.10,15 As discussed by Xu et al,18 any study using a crossover design is at risk of carryover effects mistakenly attributed to the incorrect intervention.

    Examination of funnel plots revealed marginal evidence of publication bias in the studies by McGirr et al13 and Kishimoto et al.15 A high risk of reporting bias due to incomplete data recording and protocol omission was reported by Caddy et al.10 A risk of reporting bias also was noted by Wan et al.14 They collected data on adverse events using 2 instruments. The possibility of reporting bias exists because of the potential for shared reported results.14 Papadimitropoulou et al20 lacked any mention of potential bias from any source. Pooled outcomes data from different study designs may decrease the confidence of pooled statistical analyses, as discussed by Wan et al.14

    Conclusion

    An estimated 5 to 6 million patients have depression that is resistant to conventional pharmacologic, psychologic, or somatic treatments.1 Most current therapies for TRD have a therapeutic action lag time of 2 to 6 weeks.1,2,4 Subanesthetic ketamine infusions provide rapid onset of antidepressant effect and may be a safe, well-tolerated, and effective treatment of TRD.2,5,10-20 Discontinuation of current antidepressant therapy is not necessary when one is considering ketamine infusions.16,19

    A single intravenous infusion of ketamine, 0.5 mg/kg in 100 mL of sodium chloride, administered over 40 minutes has a rapid and robust antidepressant effect,11-13,15,18,19 often apparent within 40 minutes15 to 4 hours.18 Unfortunately, the antidepressant effect of a single infusion of ketamine seems to rarely persist longer than 2 weeks.20 Ketamine’s short-term safety profile is well established, and ketamine is well tolerated.10-20 Providers must make it clear to patients that this therapy does not provide long-term alleviation of symptoms and that repeated infusions are likely necessary.24 It is particularly important to make this clear because, anecdotally, insurers rarely if ever cover the use of ketamine in treating TRD.

    Further research is needed to identify optimal dosing schedules that would best prolong the antidepressant effects of ketamine when it is administered in outpatient settings.10,13,15-19 Research studies examining longer-term use and repeated dosing are lacking.10,11,13,14,16,18,20 Long-term cost, safety, tolerance, and dependence profiles must be determined through large, parallel-group randomized controlled trials.10,11,13-19 Additionally, further research is needed to establish safety and use profiles in pediatric or geriatric populations within appropriate clinical constructs.12,15 Providers are also urged to carefully read the consensus statement from the American Psychiatric Association on the use of ketamine for treating mood disorders.24

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    2.Ionescu DF, Papakostas GI. Experimental medication treatment approaches for depression. Transl Psychiatry. 2017;7(3):e1068. doi:10.1038/tp.2017.33

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    12. Lee EE, Della Selva MP, Lui A, Himelhoch S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative analysis. Gen Hosp Psychiatry. 2015;37(2):178-184. doi:10.1016/j.genhosppsych.2015.01.003

    13. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive disorder. Psychol Med. 2015;45(4):693-704. doi:10.1017/S0033291714001603

    14. Wan L-B, Levitch CF, Perez AM, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2015;76(3):247-252. doi:10.4088/JCP.13m08852

    15. 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. doi:10.1017/S0033291716000064

    16. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: recent developments and clinical applications. Evid Based Ment Health. 2016;19(2):35-38. doi:10.1136/eb-2016-102355

    17. 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. doi:10.1176/appi.ajp.2016.16010037

    18. Xu Y, Hackett M, Carter G, Loo C, Gálvez V, Glozier N, et al. Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2016;19(4):pyv12. doi:10.1093/ijnp/pyv124

    19. Kraus C, Rabl U, Vanicek T, et al. Administration of ketamine for unipolar and bipolar depression. Int J Psychiatry Clin Pract. 2017;21(1):2-12. doi:10.1080/13651501.2016.1254802

    20. Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N. Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis. Curr Med Res Opin. 2017;33(4):701-711. doi:10.1080/03007995.2016.1277201

    21. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382-389. doi:10.1192/bjp.134.4.382

    22. Wikberg C, Petersson A, Westman J, Björklund C, Petersson EL. Patients’ perspectives on the use of the Montgomery-Asberg depression rating scale self-assessment version in primary care. Scand J Prim Health Care. 2016;34(4):434-442.

    23. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. doi:10.1136/jnnp.23.1.56

    24. Sanacora G, Frye MA, McDonald W, et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080

    AUTHORS

    Jennifer K. Lent, DNAP, CRNA, is the chief nurse anesthetist at Yukon Kuskokwim Delta Regional Hospital in Bethel, Alaska. The author was a student in the Doctor of Nurse Anesthesia Practice program at Texas Wesleyan University in Fort Worth, Texas, at the time this article was written.

    Albert Arredondo, DNAP, CRNA, is the chief nurse anesthetist at Southwestern Medical Center in Lawton, Oklahoma. He is also a co-owner of the Red River Ketamine Wellness Center in Lawton, Oklahoma. The author was a student in the Doctor of Nurse Anesthesia Practice program at Texas Wesleyan University at the time this article was written.

    Marilyn A. Pugh, PhD, is an associate professor of psychology at Texas Wesleyan University.

    Paul N. Austin, PhD, CRNA, is a professor and the coordinator of the Research and Anesthesia Curriculum for the Doctor of Nurse Anesthesia Practice program at Texas Wesleyan University.

    DISCLOSURES

    Albert Arredondo, DNAP, CRNA, is the co-owner of a healthcare facility offering the administration of ketamine for treatment-resistant depression. The other authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did discuss off-label use within the article.

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