Treatment-resistant depression (TRD) is disabling and demoralizing for patients and clinicians, with more significant burden experienced by patients. For decades, treatment for depression has relied on the monoamine theory, with medications limited in efficacy and taking a prolonged period of time to produce therapeutic effects. Even after prolonged use, only approximately 60% of patients achieve complete remission of symptoms (Mojtabai, 2017; Sinyor, Schaffer, & Levitt, 2010). Over the past decade, there has been growing recognition of the role of ketamine and other glutaminergic drugs as possible treatment for depression (Aleksandrova, Phillips, & Wang, 2017). The current article focuses on alternatives to monoamine drugs (e.g., serotonergic, adrenergic, dopaminergic drugs) as treatment for depression, with emphasis on ketamine and other developing drugs that use glutamate as the neural pathway.
The treatment choices for a client who has TRD are limited to switching to another antidepressant agent in the same class; combining medications from different classes; adding empirically supported psychotherapies to the medication; augmenting with alternative medications (e.g., lithium, a serotonin-dopamine antagonist); or using electroconvulsive therapy (ECT), transcranial magnetic stimulation, or vagus nerve stimulation (Mathew et al., 2012). In 2000, a landmark pilot study of intravenous ketamine demonstrated immediate relief of suicidal ideation and depressive symptoms following a single infusion, with results lasting up to 72 hours (Berman et al., 2000). Within the past decade, studies about infusion of ketamine at subanesthetic dosages have continued to validate this rapid remission of depressive symptoms and have spurred interest in this off-label application in psychiatric treatment (Cullen, 2017; Kraus et al., 2017). Although still not approved by the U.S. Food and Drug Administration (FDA), ketamine infusion clinics are emerging without data regarding the long-term effects, number of repeat treatment episodes, or possible tolerance and neurotoxic development. Off-label use requires clinicians to balance the benefits with the unknown long-term effects for patients who are vulnerable to a prospect of immediate relief. Whether ketamine infusions remain a viable treatment strategy, they currently provide the prospect of a novel neural mechanism to intervening in the neurobiology of psychiatric symptoms.
Ketamine has introduced the glutamate neuron as a novel mechanism to approach pharmacologically for the treatment of depression as well as other psychiatric disorders, including anxiety, obsessive-compulsive disorder, and psychotic disorders (Krystal et al., 2010). Glutamate is the predominant excitatory neurotransmitter throughout the brain and is highly complex, with eight metabotropic receptor subtypes (mGluR) and four ionotropic (ligand-gated ion channel or iGluR) receptor subtypes. The mGluR are more localized in brain distribution, modulate the iGluR, and likely have potential for future drug development and are beyond the scope of this article. The iGluR are more ubiquitous in the brain and include the receptor subtypes of N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. The current article focuses on NMDA and AMPA receptors because these are the targets for ketamine and similar drugs currently available or due to be released soon.
Throughout the 20th century, depression was seen as being due to an imbalance in the monoamines, with a focus on neurotransmission and synaptic transport between the pre- and post-synaptic neurons and a treatment focus of balancing monoamine neurotransmission. In the 21st century, however, the shift is toward depression as a disorder of synaptic plasticity, focusing on the interconnections of the brain circuity with a treatment focus of enhancing neuroplasticity (Goldberg, 2018). Although major depressive disorder is likely to be heterogenous from a neurobiological standpoint, it is associated with decreased activity in the prefrontal cortex and hippocampus and increased activity in the amygdala and nucleus accumbens. The hypothesis is that decreased synaptic activity leads to abnormally high and sustained extracellular glutamate that binds to the NMDA receptors leading to synaptic atrophy. Decreased levels of synaptic glutamate result in fewer AMPA receptor synapses and less brain-derived neurotrophic factor (BDNF). BDNF enhances neuron and synapse development. Blocking NMDA receptors contributes to an increase in AMPA and BDNF, thereby increasing neuroplasticity (Björkholm & Monteggia, 2016; Collo & Merlo Pich, 2018; Strasburger et al., 2017).
Ketamine is a dissociative anesthetic first introduced in the 1960s with the advantage of producing pain relief and sedation with minimal effect on cardiac or respiratory function. Severe behavioral adverse reactions include hallucinations, emergence delirium, and severe dissociation. Ketamine is administered intravenously (1 mg/kg to 4.5 mg/kg for anesthesia) with onset of action within 5 minutes and a half-life of 2.5 hours. Although the exact mechanism of action is still uncertain, it is reputed to be a NMDA antagonist with likely additional effects on AMPA and even dopamine. At sub-anesthetic dosage (0.4 mg/kg to 0.8 mg/kg) given intravenously over 40 minutes, ketamine produces rapid relief of depressive symptoms and suicidal thinking within 4 hours of administration (Murrough et al., 2015). A single dose can provide symptom remission from 72 hours to 4 days, even though the drug is eliminated within 3 hours (Murrough et al., 2015). The persistent effects seem to be due to the synaptic changes produced by BDNF. The most common side effects include transient perceptual disturbances, mild to severe dissociation, euphoria, and anxiety, as well as dizziness, nausea, and mild increase in heart rate and blood pressure. Long-term effects include possible ulcerative cystitis (Abdallah et al., 2016; Kraus et al., 2017).
As remarkable as ketamine seems, there remains no clear consensus for standards of care, even as ketamine clinics are opening at a steady rate throughout the United States. There are insufficient large clinical trials to indicate the frequency of dosing, number of repeat series of treatments, or long-term effects. The American Psychiatric Association (APA) published a tentative consensus statement in 2017 with the caution that the statement is not intended as a treatment guideline but rather an analysis of the current data and critical issues of ketamine use (Sanacora et al., 2017). The APA recommends a comprehensive diagnostic assessment and history of substance use and psychotic disorders, thorough history of treatment and documented antidepressant medication trials, specific physical examination and laboratory screening, careful review of the medical and psychiatric records and/or corroboration by family members, and written informed consent that includes the risks and limits of treatment and acknowledges that it is an off-label use of ketamine. Clinicians must be trained in the administration of the medication and have Advanced Cardiovascular Life Support certification. Commonly, an anesthesiologist or nurse anesthetist monitors the infusion, with a psychiatrist monitoring the patient's behavioral response and discharge readiness (Sanacora et al., 2017).
After 2 weeks of twice per week infusions, the response rate is approximately 70% based on Montgomery-Asberg Depression Rating Scale scores (Kraus, 2017). Some studies delivered treatment up to three times per week for as long as 4 weeks with minimal difference in efficacy. No studies have exceeded the 0.8 mg/kg dosage, and there are few data regarding the number of times the series can be repeated. There is the risk of cognitive impairment, cystitis, and abuse potential with chronic and frequent use of ketamine (Kraus et al., 2017; Sanacora et al., 2017).
To bypass the dissociative and psychotomimetic effects of ketamine, researchers turned to isomers including S-ketamine (esketamine), which has a four-fold affinity for the NMDA receptor (Molero et al., 2018). By rotating the molecule, the response rate was similar to intravenous ketamine: >60% improvement within 4.5 hours after a single dose with sustained effect after 24 hours and 40% response after 7 days. With two to three repeated doses per week, the response could be sustained for several weeks. Although there was transient elevation in blood pressure, there were minimal dissociative or hallucinatory effects. Esketamine can be delivered intranasally in three doses every 15 minutes two to three times per week for 2 to 3 weeks for sustained remission of depressive symptoms (Daly et al., 2018; Molero et al., 2018; Quintana, Steen, & Andreassen, 2018). Although there is a challenge in delivering the drug due to nasal physiology, it is more tolerable and convenient, especially as an adjunctive treatment with other antidepressant medications. Esketamine is currently in the FDA fast track for approval and not yet available for clinical use.
Additional Drugs on the Horizon
The study of glutamate has opened the door to several novel approaches to treatment of depression and other psychiatric disorders; many of these new drugs are on the FDA fast track for approval. Rapastinel is a partial agonist at the NMDA receptor glycine modulatory site, which is given by intravenous infusion and produces remission of depressive symptoms within 15 minutes and lasts up to 2 weeks. A possible oral formulation is in Phase 2 study (Strasburger et al., 2017; Thase, 2017).
Another potential target for adjunctive treatment is the immune system. A subset of patients with depression have high levels of C-reactive protein, an inflammatory marker, and show poor response to serotonergic agents. Preliminary studies are using such anti-inflammatory medications as COX-2 inhibitors and tumor necrosis factor inhibitors in conjunction with serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, with some early evidence of improvement with this subset of patients (Thase, 2017).
Summary and Recommendations
The monoamine approach to treating depression has been disappointing to patients and clinicians alike due to its limited efficacy and length of time to achieve therapeutic effects. Not only is TRD demoralizing, it is potentially life-threatening due to suicidal thoughts and behaviors. As brain research has pushed forward into more neural interconnectivity and plasticity, new avenues for treatment have emerged. The glutamate neuron and multiple receptors are complex and challenging to research, yet it is clear that glutamate integrates the monoamines and other neural circuits. Psychiatric nurses need to learn more about these neural pathways and the mechanisms of action that novel drugs offer. Advanced practice nurses need to approach ketamine infusion cautiously and thoughtfully. State boards of nursing are beginning to consider how nurses can incorporate ketamine and ketamine-like infusions into their scope of practice. It is tempting to jump on the bandwagon; however, ethically, the risks and benefits to a vulnerable population need to be considered. As patients read about ketamine clinics in the popular press, they may seek the advice of psychiatric–mental health nurses. As with any off-label use or new drug, we need to be prepared to offer an objective and reasoned perspective on options and referrals.
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