Ketamine in treatment-resistant depression: A review of completed investigations

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1 Original Article Ketamine in treatment-resistant depression: A review of completed investigations Abstract Shweta S. Verma Background and Objective: The objective was to evaluate clinical trial data on the use of ketamine in treating treatment-resistant depression (TRD). Materials and Methods: PubMed search (November 2012) was initiated using the keywords: Ketamine, resistant depression. Inclusion criterion included: English language publications describing clinical trial reports on humans with TRD. Results: A total of 360 patients across 15 clinical trials with TRD were treated with infusional ketamine. On average 15-90% of patients reported a >50% decrease in their baseline Montgomery-Åsberg Depression Rating Scale/Hamilton Rating Scale for Depression scores at 4 h. Response rates decreased significantly as time progressed. Conclusion: Infusional ketamine has a significant rapid, short-term antidepressant effect in the treatment of TRD. Keywords: Ketamine, Montgomery-Åsberg Depression Rating Scale score, resistant depression Introduction Treatment-resistant depression (TRD) is commonly defined as major depressive disorder (MDD) unresponsive to a minimum of 8 weeks of therapeutic doses of two different classes of antidepressants. [1] It is estimated that 30-40% of patients diagnosed with MDD are eventually classified as having TRD. [2] Therapeutic options include: Electroconvulsive therapy (ECT), transcranial magnetic stimulation, atypical anti-psychotics, lithium, and cognitive behavioral therapy. [3,4] Despite the multitude of options, treatments for TRD are limited by inefficacy, prolonged time to clinical improvement, and intolerance due to adverse effects. [5] Given the significance of TRD, and lack of definitive options, new treatments are needed. Quick Response Code: Access this article online Website: DOI: / The pathophysiology of TRD is complex and not completely understood. Among others, anatomic abnormalities in the brain s neural networks, dysfunction in intracellular signaling, ongoing aberrant gene expression, and neurotransmitter availability are implicated. [6,7] Pre-clinical data implicates glutamate as a culprit neurotransmitter. Glutamate activates neuronal receptors, including N-methyl-D-aspartate (NMDA), which promotes learning, memory, and synaptic flexibility. [8] Recently, researchers have sought to target this pathway in TRD with the NMDAglutamate receptor antagonist, ketamine. Ketamine is primarily used as a dissociative anesthetic, and is part of a drug class that includes phencyclidine. [9,10] Besides targeting the NMDAglutamate receptor, ketamine may bind opioid receptors, and modulate muscarinic receptors, voltage-gated calcium channels, and monoaminergic pathways. [9,11,12] Antidepressant properties of ketamine are thought to be due to stimulation of alpha-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid (AMPA) receptor. By antagonizing the NMDA receptor, ketamine likely diverts glutamate to activate AMPA. [8,13,14] A review of Department of Behavioral Health, Kaiser Permanente, Mid-Atlantic Permanente Medical Group, USA Address for correspondence: Dr. Shweta S. Verma, M.D. Kaiser Permanente Behavioral Health, 5999 Burke Commons Road, Burke, VA 22015, USA. shweta.verma113@gmail.com

2 56 the available clinical trial data on ketamine and its use in TRD was conducted. Materials and Methods A PubMed search (November 2012) was initiated using the keywords: Ketamine, resistant depression. Inclusion criterion included: English language publications describing clinical trial reports on humans with TRD. Publications were excluded if the treatment intent was for mood disorders other than TRD. Studies in which patients met clinical criteria for TRD, received ketamine to study its antidepressant effects, and were assessed clinically for at least 4 h postketamine were included in the review. Results Table 1 summarizes reported data on 15 clinical trials/360 patients with TRD who were treated with Verma: Ketamine in treatment-resistant depression intravenous (IV) ketamine (342 patients with openlabel enrollment, 18 patients with double-blind enrollment). All patients received the racemic mixture of ketamine infused over min, as opposed to the S-enantiomer formulation, which appears to have differing neuropharmacology. [28] In 13 trials, 326 of 360 patients received a single dose of ketamine at 0.5 mg/kg intravenously. Across all studies, response was defined as a >50% decrease in baseline Montgomery- Åsberg Depression Rating Scale ()/Hamilton Rating Scale for Depression scores. With a single ketamine infusion, overall responses ranged from 15% to 90% of patients. Besides Salvadore et al. (2012) reporting a 15% response rate (n = 14), the next lowest response rate was 40%, Salvadore et al. (2010). Across all studies, response rates decreased significantly as time elapsed (72 h to 7 days). Ketamine was generally well-tolerated with transient Table 1: Summary of various clinical trials of Ketamine in TRD References N Ketamine dose (mg/kg) Design Measures Group response rate a Zarate et al. [13] IV 1 Placebo-controlled, double-blind, crossover Machado-Vieira et al. [15] IV 1 Open-label ketamine followed by HAMD Price et al. [16] IV 1 Open label -SI 81% at 24 h Phelps et al. [17] IV 1 Open-label ketamine followed by Salvadore et al. [18] IV 1 Open-label 45% at 4 h Mathew et al. [14] IV 1 Open-label ketamine followed by 56% at 4 h 71% at 24 h 35% at 72 h 48% at 4 h Riluzole response not reported 43% at 4 h 67% with a family history of alcohol dependence 62% at 4 h 66% at 24 h 54% at 72 h No effect of riluzole on time to relapse aan het Rot et al. [19] IV (6 infusions over 12 days) Open-label 90% at 4 h 70% at 72 h Salvadore et al. [20] IV 1 Open-label 40% at 4 h Diazgranados et al. [21] IV 1 Open-label Significant improvement in depressive symptoms and SI within 4 h (% not reported) Salvadore et al. [22] IV 1 Open-label 15% at 4 h Ibrahim et al. [23] IV 1 Open-label Significant improvement in depressive symptoms at 4 h (% not reported) ECT-resistant patients with greater effect Thakurta et al. [24] IV 1 Open-label HAMD 50% at 2 h 77% at 24 h 13% at 1 week Ibrahim et al. [25] IV 1 Open-label ketamine followed by 62% at 4 h 27% at 4 weeks No effect of riluzole on time to relapse Murrough et al. [26] IV: (6 infusions, thrice weekly 12 days) Open-label 70.8% at 12 days Median time to relapse was at 18 d after last infusion Duncan et al. [27] IV 1 Open-label Significant improvement at 24 h HAMD/ = Response defined as >50% reduction in baseline score, -SI = Response defined as rating of <4. IV = Intravenous, ECT = Electroconvulsive therapy, SI = Suicidal ideation, = Montgomery-Åsberg Depression Rating Scale, HAMD = Hamilton Rating Scale for Depression

3 Verma: Ketamine in treatment-resistant depression 57 dissociative symptoms most commonly reported, and occasional blood pressure/heart rate changes requiring discontinuation. Of note, 34 patients in two of the clinical trials reviewed received up to six infusions of ketamine at 0.5 mg/kg within a 12 day period. Murrough et al. have reported on 24 of these patients, who received up to six infusions, with an overall response rate at study end of 70.8%. The median time to relapse after the final ketamine infusion was 18 days. Antidepressant response at 4 h to the initial ketamine infusion predicted response to subsequent infusions with 94% sensitivity and 71% specificity. Furthermore, 117 patients across four clinical trials were subsequently randomized to riluzole in a double-blind fashion. The objective in these trials was to maintain the initial response to ketamine over a longer period of time. Riluzole is a Food and Drug Administration approved drug used to treat amyotrophic lateral sclerosis, which inhibits the release of glutamate from the presynaptic nerve cell terminus. [25] Riluzole did not appear to maintain the antidepressant effect of ketamine in the four studies reviewed (Machado-Vieira et al. did not report riluzole efficacy). Three of 15 studies examined additional facets of TRD treatment with infusional ketamine (suicidality, patients with a family history of alcohol dependence, and ECT resistance). Price et al. studied the effect of ketamine in suicidal ideation (SI)/TRD. After a single infusion, at 24 h, -SI scores decreased by a mean of 2.08 points on 0-6 scale (P < 0.001; d = 1.37), and 81% of patients score 0 or 1 postinfusion. Implicit associations between self- and escape-related words were also reduced postketamine (P = 0.003; d = 1.36, reductions correlated across implicit and explicit measures). Next, Phelps et al. have reported on patients with TRD and a concomitant family history of alcoholism treated with a single-dose of ketamine (0.5 mg/kg IV over 40 min). A total of 26 patients were evaluated in this study, with 12 patients reporting a family history of alcohol dependence. Overall, patients with a family history of alcohol dependence had higher response rates to ketamine at 4 h (67% vs. 18%, P = 0.02). Finally, Ibrahim et al. studied 17 TRD patients that were ECT resistant and 23 TRD patients that were ECT naive. The degree of patients responding (50%) did not significantly differ between the two groups (P = 0.33). Discussion A literature review of available clinical trial data indicates that ketamine has significant and rapid antidepressant effects in patients with TRD. Infusional ketamine is also reasonably well-tolerated with the majority of patients reporting only transient dissociative symptoms. Given the prevalence of TRD, and a multitude of salvage antidepressants with varying efficacy, infusional ketamine is a promising addition to the TRD treatment armamentarium. However, it appears that the primary downside in using infusional ketamine is it s relatively short-term antidepressive effect. Across all clinical trials, responses diminished significantly 72 h after the initial ketamine infusion. Maintenance strategies to consolidate ketamine s effect have been explored, and future clinical trials should continue to target this issue. To this point, riluzole has been primarily evaluated as a pharmacotherapy to maintain infusional ketamine s high response rates. The enthusiasm for using maintenance riluzole has been its potential to enhance glutamate signaling, but studies to this point have demonstrated no benefit over placebo when given after ketamine. [14,25] Perhaps a single-dose of ketamine is inadequate. Studies evaluating five additional doses of IV ketamine suggest a more durable response than a single-dose. [19,26] Although, this would complicate outpatient treatment of TRD, this strategy should be explored further. Alternative routes of ketamine administration could potentially facilitate extended dosing. Ketamine is available in oral, intranasal, and intramuscular formulations. [9,29,30] However, it is unclear whether bioavailability would be impacted by alternative routes, or be inferior to IV ketamine s rapid reduction of depressive symptoms. [31] Although ketamine s lack of a sustained response is a potential hamper, its ability to rapidly reduce depressive symptoms could be especially beneficial in treating acutely suicidal patients across emergency rooms. [21,32] This has not been the subject of multiple studies, but limited data points to quick and significant improvement in suicide ideation scores, with one study reporting 72 h of continued response in patients with bipolar disorder. [16] Of note, a more established and studied TRD treatment is ECT, but it appears that there may be synergy between ECT and ketamine. Although propofol, thiopental, and methohexital are more commonly used for ECT anesthesia, case reports have described ketamine

4 58 Verma: Ketamine in treatment-resistant depression preceding ECT, and there is a suggestion of subsequent decreased ECT treatment frequency, and overall increased efficacy of ECT when used in conjunction with ketamine. [23,33,34] The potential mechanism may be due to decreasing of the seizure threshold and increasing the seizure duration provoked by ECT. [35] Furthermore, ketamine is promising even in ECT resistant patients as reported by Ibrahim et al. Future clinical trials will be needed to explore permutations of ketamine and ECT. Continued research will be needed to clarify the role of ketamine in the treatment of TRD. It clearly has high response rates across a broad spectrum of patients, but it appears that at least single dosing is hampered by a relatively short duration of effect. Future clinical endeavors should focus primarily on ideal dosing and maintenance strategies, as well as, exploring synergy with ECT, and its use in acutely suicidal patients. 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