International Journal of Transpersonal Studies Volume 33 | Issue 2 Article 6 7-1-2014 Ketamine and Depression: A Review Wesley C. Ryan University of Washington Cole J. Marta University of California, Los Angeles Ralph J. Koek University of California, Los Angeles Follow this and additional works at: https://digitalcommons.ciis.edu/ijts-transpersonalstudies Part of the Philosophy Commons, Psychiatry and Psychology Commons, and the Religion Commons Recommended Citation Ryan, W. C., Marta, C. J., & Koek, R. J. (2014). Ryan, W. C., Marta, C. J., & Koek, R. J. (2014). Ketamine and depression: A review. International Journal of Transpersonal Studies, 33(2), 40–74.. International Journal of Transpersonal Studies, 33 (2). http://dx.doi.org/ 10.24972/ijts.2014.33.2.40 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. This Special Topic Article is brought to you for free and open access by the Journals and Newsletters at Digital Commons @ CIIS. It has been accepted for inclusion in International Journal of Transpersonal Studies by an authorized administrator of Digital Commons @ CIIS. For more information, please contact [email protected]. Ketamine and Depression: A Review Wesley C. Ryan University of Washington Seattle, WA, USA Cole J. Marta Ralph J. Koek University of California at Los Angeles University of California at Los Angeles North Hills, CA, USA North Hills, CA, USA Ketamine, via intravenous infusions, has emerged as a novel therapy for treatment-resistant depression, given rapid onset and demonstrable efficacy in both unipolar and bipolar depression. Duration of benefit, on the order of days, varies between these subtypes, but appears longer in unipolar depression. A unique property is reduction in suicidality although data are more limited. Strategies to extend duration, via multiple doses, maintenance treatment, or subsequent augmenting medications have yielded mixed results. There is a relative paucity of data regarding alternate methods of administration such as intramuscular, intranasal, and oral routes, though preliminary results are promising. Adverse effects most reliably incl ude dissociative and sympathomimetic effects, both transient and mild, and suggest good tolerability. Ketamine's unique effects may represent an opportunity for a paradigm shift in the pharmacologic treatment of depression. Keywords: Ketamine; treatment-resistant depression; suicide; NMDA; glutamate; rapid acting; review. espite significant progress, depression remains before response is achieved. In those first few weeks, a common and disabling condition that affects antidepressant treatment may increase risk of suicidal millions, leading to increased primary care behavior, and possibly including completed suicide Dvisits and decreased productivity (Baune, Adrian, & (Björkenstam et al., 2013). With the lack of rapid Jacobi, 2007). Both psychotherapy and antidepressant response from existing medications, and indeed the pharmacotherapy are evidence-based treatments apparent risk until such response, there is urgent need recommended by experts and treatment guidelines for development of rapid acting treatment alternatives (Gelenberg et al., 2010). For those with more severe for depression (Monteggia, Gideons, & Kavalali, 2013). depression, pharmacotherapy is often required for For severe depression, electroconvulsive therapy (ECT) recovery. However, inadequate response and lack of is the only somatic intervention with the potential for remission are common, and characterize treatment- more rapid treatment effect, however concern over resistant depression (TRD; Keitner and Mansfield, adverse effects limit use. Alternative approaches utilizing 2012). The current pharmacopoeia available to clinicians direct electrical modulation, including repetitive is primarily based on modulation of serotonergic, transcranial magnetic stimulation (rTMS), trigeminal noradrenergic, and dopaminergic transmission in the brain, nerve stimulation, and deep brain stimulation (Cook, with first line agents primarily consisting of selective sero- Espinoza, & Leuchter, 2014) as well as magnetic seizure tonin reuptake inhibitors (SSRIs; Keitner & Mansfield, therapy and vagal nerve stimulation (Wani, Trevino, 2012). As demonstrated by the STAR*D study, multiple Marnell, & Husain, 2013) are promising in terms of trials of medications are frequently required to achieve efficacy, but have not been shown consistently to have a remission, and despite this, about 35% of patients remain more rapid onset of effect than pharmacotherapy. symptomatic after several successive interventions (Rush Studies suggest a role for the glutamate system et al., 2006; Olin, Jayewardene, Bunker, & Moreno, in regulation of mood (Skolnick et al., 1996; Matthews, 2012). When monoamine modulating antidepressant Henter, & Zarate, 2012; Machado-Vieira, Salvadore, medications do work, there is typically a delay of weeks Diazgranados, & Zarate, 2009), and particular promise 40 International Journal of Transpersonal Studies , 33(2), 2014, pp. 40-74 Ryan, Marta, & Koek has been generated from studies looking at the N-methyl- ketamine in humans for treatment of depression, either D-aspartate (NMDA) receptor antagonist ketamine for unipolar or bipolar, or suicidality. Those utilizing this novel indication (Artigas, 2013; Zarate et al., 2013; ketamine as an anesthetic or augmenting agent for, or in Mathew, Manji, & Charney, 2008). Ketamine was combination with, ECT or rTMS were excluded, as were developed in 1963, first tested on humans in 1964, and studies regarding the use of ketamine as an augmenting FDA approved for roles in anesthesia in 1970 (Reich et agent for psychotherapy, for purposeful alteration of al., 1989; JHP Pharmaceuticals, 2009). It was not until consciousness, or in regards to ketamine misuse. The 2000 that ketamine was concretely demonstrated in the remaining articles were further reviewed for pertinent literature to have antidepressant properties (Berman et references. Data on depression response rates were al., 2000). Ketamine has shown a large effect size, with combined and recalculated to include intent to treat onset on the order of hours, and duration of effect of (ITT) analysis, accounting for differences between rates approximately one week (Zarate et al., 2006). Reduction reported in the studies and in this review. To assess for in suicidal thoughts is further described, similarly within ongoing or planned studies a search of ClinicalTrials.gov hours of administration (Price et al., 2009; Price et al., was performed with the terms “ketamine depression.” 2014). Results A significant limitation exists in that ketamine sing the above search criteria, a total of 61 is only FDA-approved for intravenous (IV) or intra- Upublications from PubMed.gov and 96 from muscular (IM) use in induction or maintenance of ClinicalTrials.gov were identified for inclusion in this anesthesia, making administration in less controlled review. settings difficult. While most studies on ketamine thus Study population and methodology far have looked at longer IV infusions, other routes have Of these 61 studies, 46 utilized the IV route shown promise for increasing patient access to ketamine of administration, accounting for over 450 patients in (Larkin & Beautrais, 2011; Harihar, Dasari, & Srinivas, total. A further 18 studies utilized IM, oral, intranasal, 2013; Lara, Bisol, & Munari, 2013; Lapidus et al., 2014; sublingual, or subcutaneous treatment in over 100 Iglewicz et al., 2014). patients. Nearly all publications reported use of racemic This article reviews the extant literature ketamine, with only 13 patients in total receiving regarding use of ketamine as an antidepressant, S-ketamine (Denk, Rewerts, Holsboer, Erhardt- highlighting its role as a rapid acting agent for unipolar Lehmann, & Turck, 2011; Paul, Schaaf, Padberg, and bipolar depression. We report on and analyze efficacy, Moller, & Frodl, 2009; Segmiller et al., 2013; Paslakis, with additional attention to durability of response, Gilles, Meyer-Lindenberg, & Deuschle, 2010). Most improvement in suicidality, routes of administration, studies utilized only one administration of ketamine, dosing protocols, and safety. Different stereoisomeric though five open label investigations (OLI) and one forms of ketamine are also reviewed given the possibility randomized control trial (RCT) did assess multiple that one form may be associated with fewer dissociative doses, from one to three times per week, for up to three effects. We conclude with recommendations for weeks. The majority of publications reported on patients future study design as well as potential off-label use with unipolar depression, though bipolar depression in less structured settings. Detailed discussions on the was also represented in ten. Given the differences in history and neuropharmacology of ketamine, and the presentation, etiology, and response between these two glutamate theory of depression are not included; the types of depression, these are considered separately. Save reader is referred to previous publications on these topics for a minority of case studies (Table 5; Suppl. Table 1), (Domino et al., 2010; Krystal, Sanacora, & Duman, articles utilized one or more validated depression rating 2013; Caddy. Giaroli, White, Shergill, & Tracy, 2014; scales, including the Montgomery-Åsberg Depression Naughton, Clarke, Olivia, Cryan, & Dinan, 2014). Rating Scale (MADRS; Montgomery and Åsberg, 1979), Materials and Methods