Developing technique could reduce emotional distress and risk of self-harm within minutes after infusion.
Despite our best efforts, management of suicidal patients in the ED generally leaves both patient and provider less than satisfied. These patients often arrive in the ED as a result of a long, knotted string of psychosocial and emotional stressors that are well beyond our ability to untangle. The demands of a busy ED and the gentle, slow manner required to truly engage these individuals are a poor match. Historically, this has meant that the EP’s role has been limited to medical clearance, a prolonged, laborious process that is helpful to a very small minority of patients. (1,2).
This may change. Several recent small studies, some performed in the ED setting, have demonstrated that ketamine given to acutely suicidal patients can reliably decrease their suicidal ideation and depression (3-10). The effects are seen as soon as 40 minutes after infusion and can last up to 14 days (4). Although it isn’t fully clear yet where this will fit into emergency management, it is beginning to appear that ketamine may give us a more active role in mitigating the patients’ emotional distress and reducing self-harm risk.
Benefits of Ketamine Use
Ketamine has been under investigation as a rapid-acting antidepressant for over a decade. Unlike traditional antidepressants that require many weeks to provide relief, ketamine’s benefits are almost immediate. Furthermore, ketamine seems to relieve depression symptoms in patients who have failed standard antidepressant therapy (8). The protocol used by most of these investigators is fairly simple: a 0.5 mg/kg IV infusion given over 40 minutes (3,4,8.9). This has been studied for both suicidality and treatment-resistant depression. The most rigorous of these studies, published at the end of 2017, examined depressed patients recruited from the community using a randomized, placebo-controlled design (3). Patients were screened using standard psychiatric diagnostic inventories. Eighty patients identified as depressed and suicidal were enrolled and admitted to a psychiatric inpatient setting for study treatment.
These patients were randomly assigned to receive either ketamine or midazolam. The latter was chosen to augment blinding, since a completely inert substance such as saline would have been too easy to distinguish from ketamine. Those that received ketamine decreased their score on a suicidality inventory by more than half, whereas those that received the midazolam had only a modest drop. They then gave the non-remitters in the midazolam group a ketamine infusion. These subjects saw an improvement similar to the original ketamine cohort.
Three studies, all performed in the emergency setting, have experimented with a lower dose, 0.2 mg/kg slow IV push (5,6,10). While each of these studies found a reduction in suicidality, interpreting them as a whole is problematic for a number of reasons. First, they were small studies. Second, they used different rating scales for their outcomes, thereby obscuring the definition of what constitutes success. Lastly, one of the studies(5) reported concerns about their data collection. Until a high-quality dose comparison study is done in the ED setting, we cannot say that the lower dose should be considered equivalent.
Risk Factors
As with all therapies ketamine involves certain risks. Fortunately, most EPs are familiar with these as a result of having administered this medication for years for procedural sedation and, more recently, analgesia. Cardiovascular risks such as dysrhythmia or hemodynamic instability are rare at these doses. Infrequent reports of psychiatric side effects such as mild dissociation are reported in the psychiatric literature, which reflects the experience within our specialty. EPs offering this treatment would, of course, follow the protocols established at their own hospitals, but the ACEP guidelines on sub-dissociative dose ketamine state, “due to SKD’s excellent safety profile and activity as an analgesic, not an anesthetic, special administration procedures and/or monitoring are not required.”(11)
There are some circumstances in which benefit would be less certain and risk greater. For instance, we have yet to fully investigate how psychotic patients or patients with a history of psychosis would respond. There are differing opinions on whether we should expect such patients to do better or worse with this treatment. One group of investigators found that schizophrenic patients showed an increase in psychosis with ketamine infusion, although this resolved within 90 minutes (12). Others have reported an improvement in psychotic symptoms when patients with psychotic depression were treated with ketamine, but these were very small case series (13, 14). Therefore, until we have more experience using ketamine for SI, a history of schizophrenia, schizoaffective disorder or other psychotic disorder should be considered a contra-indication. Similarly, patients manifesting hallucinations, delusions or agitation and disorganized thinking should not be treated with ketamine for SI.
There also exists a theoretical concern of paradoxically increasing certain patients’ risk of self-harm. If clinicians or insurance companies base their assessment of the patient’s need for ongoing psychiatric hospitalization on the presence of suicidality, it is possible that the patient might be discharged prematurely. The anti-suicidal benefits of ketamine peak at 24 hours, but can last a week or more. However, it is conceivable that a patient’s suicidal impulses could be suppressed just long enough to be discharged from psychiatric care, but then recur after they are no longer under close supervision. This has not occurred in any of the trials performed to date. However, as this is a novel therapy, it might be prudent for the EP to communicate this concern to the receiving psychiatrist to avoid such a situation.
Medical issues such as a history of adverse reaction to ketamine or acute uncontrolled hypertension or tachycardia would all be reasons to withhold the therapy. All trials to date have excluded intoxicated patient, so we are certainly not in a position to endorse use in this population. Patients with a history of ketamine or PCP abuse might not be ideal candidates either. First, administration could trigger relapse. Second, such patients have often developed tolerance to ketamine and, therefore, might not respond to standard doses.
Outlook for the Future
For many suicidal patients, ketamine appears to be a promising therapy. As we would presumably be transferring these patients to a locked psychiatric unit, one might question the benefit of decreasing SI since they will be in a protected setting anyway. It is important to bear in mind that suicidal depression is a profoundly painful emotional experience. As physicians we have the same responsibility to relieve this suffering as we do physical pain. Additionally, the benefits of treating depression and suicidality can be expected to extend beyond immediate symptom relief. Because patient safety is a priority in treatment, by mitigating the risk of self-harm one allows the care in the psychiatric unit to focus on deeper issues more likely to sustain healthy functioning rather than simply preventing physical injury. Furthermore, depression in itself inhibits higher cognitive function. Depressed patients have difficulty with problems solving and abstract thought. They also experience impairment in motivation. Improvement in depression, therefore, would allow them to participate more actively in psychotherapy and plan changes in their lives moving forward.
One might also wonder whether EP’s should be in charge of a psychiatric treatment that has little impact on the patient’s medical emergency department concerns. However, EPs are the only doctors in these patients’ chain of care that are familiar and comfortable with ketamine and have the resources to monitor its use. Most psychiatrists have never given ketamine and are not in a setting where appropriate monitoring can be performed with ease, even if they consulted anesthesia to do the infusion. So, although we might not see the direct benefit while the patient is under our care, EPs may still be the physicians most qualified to administer this treatment.
So, are we there yet? Despite promising early studies, it is too early to recommend this as standard therapy. We are only now beginning to see the quality research that would allow EPs to independently offer ketamine for this indication. Yet this is a population that is suffering and our current practice offers limited relief.
This may be the time when EDs begin collaborating with their hospitals’ psychiatry departments to develop protocols for administration to the appropriate individuals, as we in the process of doing where I work. Having spoken with physicians running ketamine clinics in New York City, I can tell you that they are seeing successful treatment of thousands of non-suicidal, depressed patients annually. This is a therapy that is already being used with confidence in other settings. Once we put the pieces in place, we, too, may be in a position to offer real treatment to a population in need.
References
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[2] Parmar P. el al. Value of mandatory screening studies in emergency department patients cleared for psychiatric admission. West J Emerg Med. 2012 Nov;13(5):388-93
[3] Grunebaum, M. et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: a Midazolam-controlled Randomized Clinical Trial. Am J Psychiatry. 2017 Dec 5 [Epub ahead of print]
[4] DiazGranados N. Rapid Resolution of Suicidal Ideation after a Single Infusion of an NMDA Antagonist in Patients with Treatment Resistant Major Depressive Disorder. J Clin Psychiatry, 2010 December. 71(12):1605-1611.
[5] Burger J. et al. A Double-Blinded, Randomized, Placebo-Controlled Sub-Dissociative Dose Ketamine Pilot Study in the Treatment of Acute Depression and Suicidality in a Military Emergency Department Setting. Military Medicine. 2016. 181(10):1195.
[6] Larkin G, Beautrais A. A preliminary naturalistic study of low dose ketamine for depression and suicide ideation in the emergency department. International Journal of Neuropsychopharmacology, 2011. 14:1127-1131.
[7] Price R. Effects of Intravenous Ketamine on Explicit and Implicit Measures on Suicidality Treatment-Resistant Depression. Biological Psychiatry, 2009. 66:522-526.
[8] Murrough J. et al. Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression. American Journal of Psychiatry, 2013. 170(10)1134-1142.
[9] Vande Voort J. et al. Continuation phase intravenous Ketamine in adults in adults with treatment-resistant depression. Journal of Affective Disorders, 2016. 206:300-304.
[10] Kashani P. et al. The effect of intravenous ketamine on suicidal ideation in emergency department patients. Emergency (Tehran), 2014. 2(1):36-9.
[11] www.acep.org/Clinical—Practice-Management/Sub-dissociative-Dose-Ketamine-for-Analgesia/#sm.001i1s1hh10okf0yrad1b43g9y9vd
[12] Lahti A. et al. Effects of Ketamine in Normal and Schizophrenic Volunteers. Neuropsychopharmacology, 2001. 25(4):455-467.
[13] da Frota Ribiero C. el al. The Use of Ketamine for the Treatment of Depression in the Context of Psychotic Symptoms [letter]. Biological Psychiatry, 2016. 79:e65.
[14] Pennybaker S. et al. Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry, 2017. 82:e35-36.