Research paperLow-dose ketamine for treatment resistant depression in an academic clinical practice setting
Introduction
Clinical depression is a prevalent debilitating psychiatric illness involving physical, mood, and cognitive symptoms. It has been reported that approximately 7.6% of the United States (US) population over the age of 12 experience depression over any given two week period (Pratt, 2014) and despite the increasing number of antidepressant medication prescriptions, suicides in the United States increased by 24% between 1999 to 2014, making it the 10th leading cause of death overall in the United States (Curtin et al., 2016).
Approximately one-third of patients with major depression fail to adequately respond to serial trials of currently approved antidepressants, which all share the primary effect of modulating monoamine neurotransmission (Sinyor et al., 2010). While the definition of Treatment Resistant Depression (TRD) is variable, literature has commonly defined the condition as failure of at least two trials of first line antidepressants of both adequate duration and dose (Al-Harbi, 2012). There are limited treatment options for TRD. Electroconvulsive Therapy (ECT) is currently considered the gold standard for TRD, however is limited by cognitive side effects as well as need for anesthesia and seizure induction. Repetitive transcranial magnetic stimulation (rTMS) is a more recent option for TRD which is better tolerated than ECT but may take longer to exhibit efficacy (Xie et al., 2013).
Several recent studies have demonstrated that a single infusion of low-dose ketamine significantly reduces symptoms of depression within 24-h in TRD patients with Major Depressive Disorder (MDD) or Bipolar Affective Disorder (BD) (Iadarola et al., 2015, Romeo et al., 2015, Xu et al., 2015b). A review of studies investigating low-dose ketamine found that aggregated response rates (≥ 50% reduction from the baseline score on a validated depression rating scale) in randomized controlled trials as well as open label studies were 61% (Kraus et al., 2017).
These findings represent an unprecedented average response rate and speed of efficacy for a depression treatment, let alone a treatment for TRD and they have, understandably, led to great interest in the possibility that ketamine, or another drug designed to mimic ketamine's mechanism of antidepressant action, may represent an effective and rapid treatment for TRD. However, the aforementioned prospective published studies generally selected subjects who met a priori determined inclusion and exclusion criteria. For example, most of these studies either only included patients who were willing and able to discontinue their psychotropic medications (Berman et al., 2000, Murrough et al., 2013, Valentine et al., 2011, Zarate et al., 2006) or severely limited allowed medications (Chilukuri et al., 2014, Diazgranados et al., 2010, Ghasemi et al., 2014, Lapidus et al., 2014, Larkin and Beautrais, 2011, Rybakowski et al., 2013, Shiroma et al., 2014, Sos et al., 2013, Zarate et al., 2012). A history of suicidal behavior, active suicidal ideation, and comorbid psychiatric conditions other than anxiety were typically exclusionary in the earlier studies of ketamine for TRD.
It has been shown that subjects recruited for clinical trials in depression are poorly representative of outpatients who seek treatment for depression. Indeed, it has been estimated that 86% of outpatients with clinical depression would not qualify for a typical clinical trial in depression due to exclusion criteria and that candidates who would be excluded are more chronically ill and have greater psychosocial impairment (Zimmerman et al., 2005, Zimmerman et al., 2002).
As evidence accrued demonstrating ketamine’s safety and its efficacy in reducing suicidal ideation, the inclusion and exclusion criteria of clinical studies investigating ketamine’s antidepressant effects have become less stringent. Nevertheless, even these recent studies have subject eligibility criteria that are not representative of patient selection criteria in real -world clinical practice. (Singh et al., 2016; Cusin et al., 2017, Vande Voort et al., 2016). In some recent studies, suicidal ideation is an inclusion requirement rather than an exclusion criteria as it was in earlier studies. (Cusin et al., 2017, Vande Voort et al., 2016).
Given the strong interest in ketamine's potential as a treatment for TRD based on the highly positive results obtained in published clinical trials, it is important to investigate its efficacy and safety in patients who are more representative of the TRD population.
In this regard, it is notable that at least three open label studies investigated the effects of IV low-dose ketamine in a TRD sample that did not exclude suicidal ideation or concomitant medication. The reported response rates in these studies were 11–25% after a single infusion (Rasmussen et al., 2013, Diamond et al., 2014, Shiroma et al., 2014), a rate much lower than reported in studies that had more restrictive eligibility criteria, and at least one of these reported a significantly higher rate of adverse events as well (Diamond et al., 2014). These findings raise questions about the generalizability of the prospective controlled and open-label studies which showed robust efficacy and tolerability of ketamine in carefully selected TRD subjects.
Based on the published studies suggesting robust and rapid efficacy along with established safety of sub-anesthetic ketamine, an outpatient ketamine treatment program for patients with TRD was developed by one of the authors (DF) at University of California at San Diego (UCSD). In this paper, we report the results of a retrospective analysis of the safety and efficacy of the initial ketamine infusion administered to a cohort of patients in this program.
Section snippets
Patient selection for ketamine treatment
Patients who received ketamine infusions were generally self-referred or referred by their treating psychiatrist for consideration to receive ketamine treatment for TRD. Candidates were interviewed by the prescribing psychiatrist (author DF) to assess the severity of their depression as well as the extent and outcome of previous treatment trials. As is typical for a clinical practice, the criteria for accepting any patient for ketamine treatment in this clinical program was the determination of
Sample demographics
Of the first 50 patient charts examined, 41 met inclusion criteria for this analysis. Eight patients were excluded due to missing either a baseline or 24-h BDI score and one patient was excluded due to being < 18 years of age. Excluded charts were reviewed for serious adverse events of which none were identified. Subjects mean age was 48.6 ± 12.73 years. Demographic variables including gender and ethnicity are displayed in Table 1. All patients had failed therapy with at least four
Discussion
In this retrospective study, we evaluated the efficacy and safety of an initial 0.5 mg/kg, 40-min intravenous ketamine infusion in a sample of TRD patients treated as part of an outpatient academic clinical practice. We believe this to be the first report of ketamine infusion treatment for TRD patients participating in a clinical practice (rather than prospective research), although a retrospective report of oral ketamine treatment in a depressed hospice population has been reported (Irwin et
Acknowledgements
None.
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A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions
2021, Journal of Affective DisordersCitation Excerpt :The CADSS-6 was strongly correlated at each infusion with the longer version of the CADSS supporting the assertion that the CADSS-6 captures the dissociative symptoms reported in patients receiving IV ketamine. Although existing studies indicate that dissociation severity attenuates with repeated infusions, the sample herein exhibited an increase in symptoms during the third and fourth infusion (Feifel et al., 2017; Phillips et al., 2019; Short et al., 2018). Previous analysis of this sample has indicated that the increase in dissociative symptoms is a function of the dose increase (to 0.75 mg/kg) received at the third infusion (Rodrigues et al., 2020).
A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019
2020, Journal of Affective DisordersCitation Excerpt :More details are presented in the Supplemental File D. Sixteen studies provided data to calculate weighted effect size averages of depression scores following a single infusion of 0.5mg/kg ketamine (Abdallah et al., 2017; Berman et al., 2000; Carlson et al., 2013; Chen et al., 2018a; Diazgranados et al., 2010; Fava et al., 2018; Feifel et al., 2017; Grunebaum et al., 2018; Ibrahim et al., 2011; Murrough et al., 2013a; Rybakowski et al., 2017; Salvadore et al., 2012; Sos et al., 2013; Thakurta et al., 2012a; Thakurta et al., 2012b; Zarate et al., 2006) for a total of 518 participants. The results show a strong effect within 24 hours (1.012) and at 24 hours (0.96) post-infusion.