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Recent research has shown that ketamine has considerable promise for treating a wide range of treatment-refractory neuropsychiatric disorders, including obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bipolar disorder, suicide ideation, addiction and, most notably, treatment-resistant major depressive disorder (MDD). Although this research has taken place almost exclusively within the past two decades, evidence of ketamine’s neuropsychiatric effects appeared long before this. For example, ketamine was used throughout the 1970s in Mexico as part of psychedelic therapy sessions that combined traditional healing practices with psychoanalytic techniques.
In 2000, researchers found that ketamine had strong, fast-acting, and long-term effects in depression. In a randomized, placebo-controlled, crossover design study, patients with depression received 0.5 mg/kg of ketamine or saline on the first day of testing. Treatments were switched 1 week later. Researchers found that the antidepressant effects of ketamine began within 4 hours, peaked at 72 hours, and lasted for 1 to 2 weeks thereafter.1 In a 2006 study, this finding was replicated in an independent group of 18 patients with major depressive disorder who were resistant to other treatments. Compared with participants who received placebo, those who received ketamine showed significant improvement in symptoms within 110 minutes, with 35% maintaining significant response for at least 1 week.
Many of today’s depression treatments are monoaminergic-based, including monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. These treatments have been proven effective for a large number of patients. However, a significant subset of patients with major depressive disorder do not respond to these agents. Despite its undisputed value to the field, the monoamine hypothesis of depression cannot fully explain the heterogeneity of MDD. In the 1990s, animal models began to implicate glutamate – one of the major excitatory neurotransmitters in the mammalian central nervous system (CNS) – as well as its ionotropic NMDA receptor in the etiology and treatment of mood disorders .
Existing antidepressant treatments [MAOIs, TCAs, SSRIs, and serotonin-norepinephrine reuptake inhibitors (SNRIs)] are monoaminergic-based treatments. Although they have been in use for decades and have helped many patients, a significant subset of MDD patients showed little to no therapeutic benefit in response to these agents. For instance, the NIMH-funded, communitybased Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of >4000 MDD patients found that, even after four unique medication trials, augmentation, or switch, 33% of the patients did not respond to standard monoaminergic-based treatments .
In 2000, Berman and colleagues discovered that ketamine exerted rapid, robust, and relatively sustained antidepressant effects in depressed patients . Using a randomized, placebo-controlled, crossover design, each patient received an i.v. infusion of 0.5 mg/kg of either ketamine or saline on the first test day. On the following test day, which took place at least 1 week later, treatments were switched. The authors found that ketamine exerted antidepressant effects that began within 4 h of the infusion, peaked at 72 h, and persisted for 1–2 weeks post-infusion. .Ketamine has also been shown to have distinct and independent antisuicidal and anti-anhedonic effects in patients with mood disorders .
Another limitation of currently available antidepressants is that their clinical effects take more time to reach their full therapeutic potential (for instance, the mean onset for paroxetine is 13 days). This is a substantial disadvantage during an acute depressive crisis. Furthermore, even when these agents do alleviate depressive symptoms, evidence regarding their ability to successfully reduce suicide ideation and behavior remains inconclusive . In contrast, a single dose (0.5 mg/kg) of i.v. ketamine exerts rapid and profound antidepressant effects within hours to days of administration . Ketamine also rapidly reduces suicidel ideation, an effect that appears to occur independently of its antidepressant properties . Ketamine has dose-dependent neuropsychological effects even at subanesthetic doses, with antidepressant properties peaking at 0.5–1.0 mg/kg.
Ketamine’s pan-therapeutic effects also include alleviating fatigue and anhedonia as well as improving sleep measures such as circadian rhythm and slow-wave activity in MDD patients .
The positive effects of Ketamine has led to research into other rapidly acting antisdepressants, including nasal ketamine. Lapidus and colleagues demonstrated that intranasal ketamine had antidepressant effects and led to sufficiently high ketamine plasma concentrations. We use a compounded intranasal ketamine miuxture in our office at NOVA Health Recovery. There is also an FDA approved version more recently, which has only the S-Ketamine in it . There are heavy restrictions and high costs to the FDA approved version, yet efficacy may not be any better.
Noitrois Oxide also has antidepressant effects. Like ketamine, it exhibits NMDA receptor antagonism, has partial agonism for mu, kappa, and delta opioid receptors, inhibits AMPA, kainite, and gamma-aminobutyric acid receptors A and C (GABAA, GABAC), affects serotonin-3 receptors (5-HT3), and releases dopamine . In a double-blind, placebo-controlled, crossover trial, depressive symptoms improved for participants receiving nitrous oxide within 2 h compared with those receiving placebo, an effect that remained significant at 1 day post-treatment. Phase I and II trials are ongoing to determine optimal dose, safety, and efficacy.
Sarcosine also has antidepressant effects. t, sarcosine (also known as N-methylglycine), is an amino acid that functions as a glycine transporter-1 inhibitor and a 6- week, double-blind, randomized, citalopram-controlled trial in 20 MDD patients found that sarcosine possessed superior antidepressant properties compared with citalopram after 2 weeks . Notably, and in contrast to ketamine, sarcosine did not result in rapid-acting effects on the timescale of several days. Sarcosine has co-agonistic properties at the NMDA receptor and is an agonist at the inhibitory glycine receptor. It also exhibits NMDA-enhancing properties, suggesting that AMPA-receptor-mediated or other downstream mechanisms might elicit antidepressant effects. NMDA receptor downregulation might also play a part .
Suboxone (Buprenorphine) also has antidepressant effects as well. Intrigued by the potential of nonaminergic antidepressant mechanisms, researchers have begun to re-evaluate the role of endogenous opioids in depression. For instance, buprenorphine (BUP), a drug currently used to treat opioid addiction and pain disorders, is being explored as a treatment for MDD. The compound has a wide variety of actions throughout the brain, including partial agonism at the mu opioid receptor and antagonism at the kappa and delta opioid receptors ; these are connected to intracellular signaling cascades that potentially mediate antidepressant effects Several open-label studies of BUP in MDD have shown promising preliminary results, and a double-blind, randomized, placebo-controlled trial examining the effect of low-dose BUP on suicidal ideation similarly yielded positive results .
NOVA Health Recovery has used buprenorphine succesfully in the treatment of depression.
Ketamine and Future Depression Treatments
1. Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA Jr. The influence of ketamine on drug discovery in depression [published online August 2, 2019]. Drug Discov Today. doi: 10.1016/j.drudis.2019.07.007
2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.
3. Nagele P, Duma A, Kopec M, et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biol Psychiatry. 2015;78(1):10-18.