The amino acid glutamate is the major excitatory neurotransmitter in the brain, and it has important roles in many normal and abnormal physiological processes (Kugaya & Sanacora, 2005). Similar to other neurotransmitters, glutamate is released from nerve cells, binds to receptors, and is removed by reuptake transporters. Glutamate receptor systems are complex, and they are segregated into distinct receptor subtypes according to their molecular and pharmacological properties. The two main classes of glutamate receptors are referred to as ionotropic and metabotropic. Ionotropic glutamate receptors are classified into three groups (each having multiple subtypes): N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate. Drugs can potentially bind to different glutamate receptor subtypes and therefore modulate glutamate function in different ways. Certain NMDA receptor antagonist drugs have antidepressant effects in animal models of depression. Ketamine (Ketalar®), an anesthetic agent derived from the hallucinogenic drug phencyclidine (PCP), is a high-affinity NMDA receptor antagonist that also binds to opioid mu and sigma receptors (Wolff & Winstock, 2006). Ketamine is being intensively investigated as an antidepressant therapy (Aan Het Rot, Zarate, Charney, & Mathew, 2012) and some of the studies are reviewed below.
Ketamine for Major Depression
Berman et al. (2000) conducted the first randomized, double-blind, placebo-controlled, crossover study investigating the short-term effects of a single dose of ketamine in seven individuals with major depression. The individuals received intravenous (IV) treatment with a single subanesthetic dose of ketamine (0.5 mg per kg of body weight) or saline on two separate testing days at least 1 week apart. Individuals randomized to receive ketamine on the first testing day received saline during the second testing day and vice versa. Compared to saline infusion, ketamine infusion resulted in a significant reduction in depression symptom scores (based on the Hamilton Depression Rating Scale [HDRS]) after 4, 24, 48, and 72 hours.
In a second similarly designed, randomized, double-blind, placebo-controlled, crossover study, IV ketamine (0.5 mg/kg) or saline was given in a single dose 1 week apart to 18 patients with treatment-resistant depression (TRD) (Zarate et al., 2006). Half the patients randomly and blindly received ketamine for the first dose and placebo for the second dose; half received placebo first and ketamine second. Compared to saline, ketamine was associated with a significant improvement in depression (based on the HDRS) after 2 hours, 4 hours, and 1, 2, 3, and 7 days.
Valentine et al. (2011) conducted a study in 10 patients with major depression, who were all first given a single dose of saline and then a single dose of ketamine (0.5 mg/kg) in a fixed order, 1 week apart, under single-blind conditions. The HDRS rating scale was administered before, during, and after each infusion. Significant improvement in depression was noted after 1 hour and 1, 2, 3, 5, and 7 days for ketamine compared to saline.
Ibrahim et al. (2011) investigated the effects of a single IV dose of ketamine (0.5 mg/kg) in an open-label study of 40 patients with TRD, according to their treatment history with electroconvulsive therapy (ECT). This study compared 17 patients with TRD who previously did not respond to ECT and 23 patients with TRD who had never received ECT. Patients were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline and 40, 80, 120, and 230 minutes after infusion. After 230 minutes, depressive symptoms were significantly improved in the ECT-resistant group with a moderate effect size (a measure of the magnitude of the effect), whereas the non-ECT exposed group showed significant improvement with a large effect size. These findings suggested that ketamine is effective in patients with TRD, even among those patients who had previously not responded to ECT.
Ketamine for Bipolar Depression
Diazgranados et al. (2010) conducted a randomized, double-blind, placebo-controlled, crossover study in 18 patients with treatment-resistant bipolar depression who were taking lithium or valproate. Patients received a single IV infusion of ketamine (0.5 mg/kg) or saline on two separate testing days 2 weeks apart. The MADRS was used to rate patients at baseline, after 40, 80, 110, and 230 minutes, and after 1, 2, 3, 7, 10, and 14 days. Within 40 minutes, depressive symptoms significantly improved for ketamine compared to saline and this improvement remained significant through Day 3. From Days 7 to 10, however, the effects of ketamine began to wane and no significant difference was noted compared to placebo. Although 71% of patients responded to ketamine and 6% responded to saline at some point during the 2-week trial, the study suggested that the beneficial effects of a single dose of ketamine are not sustained over time.
Zarate et al. (2012) conducted a replication of this study in an independent sample of 15 patients with treatment-resistant bipolar depression taking lithium or valproate. In this randomized, double-blind, placebo-controlled, crossover study, patients received a single IV infusion of ketamine (0.5 mg/kg) or saline on two separate test days 2 weeks apart. Similar to the Diazgranados et al. (2010) study, depressive symptoms significantly improved for ketamine compared to saline from 40 minutes post-infusion through Day 3, but from Days 7 to 10 the effects of ketamine waned and no significant difference was noted compared to placebo. At some point during the 2-week trial, 79% of patients responded to ketamine and no patient responded to saline. This study also reported a rapid reduction in suicidal thoughts.
Rybakowski, Permoda-Osip, Skibinska, Adamski, & Bartkowska-Sniatkowska (2012) investigated the effects of a single IV dose of ketamine (0.5 mg/kg) in an open-label study of 25 patients with treatment-resistant bipolar depression taking mood-stabilizing medication. Treatment response was defined as a ⩾50% reduction on the HDRS and remission was defined as a score of ⩽7 on the HDRS. The ketamine response/remission rates, respectively, were 4%/0% (after 6 hours), 24%/16% (after 24 hours), 52%/32% (after 7 days), and 52%/48% (after 14 days).
Relapse Prevention Following Intravenous Ketamine
Although single doses of ketamine have rapid antidepressant effects that last for up to 1 week, the extent and duration of this antidepressant effect over longer periods has not been well-characterized under controlled conditions. Riluzole (Rilutek®), an approved treatment for amyotrophic lateral sclerosis, inhibits the release of glutamate, may have indirect effects on AMPA and kainate receptors, and may increase the reuptake (removal) of glutamate. Open-label studies have suggested that it may be effective and well tolerated in patients with TRD and bipolar depression, but no controlled studies have been reported. In a controlled study, riluzole was not significantly better than placebo for preventing relapse among a group of 26 ketamine-responsive patients with TRD (Mathew et al., 2010).
Ibrahim et al. (2012) investigated the extent and time course of antidepressant improvement during a 4-week follow up after a single IV dose of ketamine (0.5 mg/kg) in 42 patients with TRD. Four to 6 hours post-infusion, patients were randomized to double-blind treatment with riluzole or placebo for 4 weeks. Depressive symptoms were rated daily (using the MADRS). A significant improvement in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 4-week trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks. The average time to relapse was approximately 13 days. No difference was noted between the riluzole and placebo treatment groups on relapse rates.
Ketamine Treatment of Suicidal Symptoms
As described in the study by Zarate et al. (2012), IV ketamine was associated not only with a rapid antidepressant effect, but also an early effect on reducing suicidal thoughts. Price, Nock, Charney, & Mathew (2009) investigated the effects of a single IV dose of ketamine (0.5 mg/kg) on suicidality in 26 patients with TRD, using the suicidality item of the MADRS (MADRS-SI). In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period. At 24 hours after infusion, MADRS-SI scores were significantly reduced by an average of 2.08 points on a scale of 0 to 6, and 81% of patients received a rating of 0 or 1. MADRS-SI reductions were significant and sustained for 12 days in the nine patients receiving repeated-dose ketamine.
Larkin and Beautrais (2011) examined the efficacy of a single IV dose of ketamine (0.2 mg/kg) in 14 depressed emergency department patients with suicide ideation. Patients were monitored for 4 hours and contacted daily for 10 days. Treatment response and suicidality was evaluated using the MADRS. Mean MADRS scores decreased significantly by 4 hours. Suicide scores on the MADRS also decreased significantly and were sustained during the 10-day follow up.
Tolerability and Safety of Ketamine
As a structural derivative of the drug PCP, ketamine has amnestic (cognitive and memory impairment), anesthetic, and analgesic properties. A potential safety concern with the use of ketamine is its abuse liability. Ordinarily, ketamine is used at higher doses as an anesthetic agent, and it has been used successfully as part of the usual procedure for administering ECT (Okamoto et al., 2010). With single subanesthetic doses (as used in the depression treatment studies), ketamine appears to be relatively safe and well tolerated. Adverse effects described in these studies include transient headache, dizziness, vital sign changes, euphoria, confusion, and dissociative effects (perceptual disturbances). Because the short-term antidepressant effects of ketamine might not be sustained over longer periods of time, treatment strategies using repeated or intermittent dosing may be necessary. Whether such a dosing strategy is effective or continues to be effective (i.e., tolerance to the anti-depressant effect does not develop) is unknown. Moreover, the long-term adverse effect profile of single or repeated subanesthetic doses of ketamine needs to be determined. The anticonvulsant lamotrigine (Lamictal®), an approved treatment for bipolar disorder, decreases glutamate release. In a placebo-controlled study of 16 normal individuals given subanesthetic doses of ketamine, lamotrigine plus ketamine (compared to placebo plus ketamine) significantly decreased the perceptual disturbances associated with ketamine and significantly increased the immediate mood-elevating effects of ketamine (Anand et al., 2000). Whether lamotrigine (unlike riluzole) can improve the tolerability or long-term efficacy of ketamine in depressed patients is unknown.
Studies clearly demonstrate that IV ketamine is safe and has a rapid and profound short-term effect on depressive symptoms, including suicidality, even among patients considered treatment-resistant to standard medications or ECT. The long-term safety and effectiveness of ketamine need to be determined before it can be incorporated into clinical practice. Although the effectiveness of alternative routes of ketamine administration (i.e., oral, intranasal, or intramuscular) needs to be determined, IV ketamine could be conceptualized as a clinic-based procedural therapy and nurses should become familiar with the drug.
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