Ketamine as a Novel Therapy for Depression, Term Paper Example

Ketamine as a Novel Therapy for Depression: NMDA Receptor Antagonists and their Antidepressant Activity

Introduction/Background

The Food and Drug Administration approved the drug ketamine to treat severe depression in patients. This version of ketamine is administered to patients as a nasal spray.

Hypothesis

The mode of action in NMDA receptor antagonists such as ketamine and its S-enantiomer –esketamine contributes to a quicker response to the treatment of depression spread across pre-frontal cortex and medial temporal cortex.

Methods

• Experiment to determine the mood states of patients on administering ketamine.
• Micro-dialysis measurement of the brain neurotransmitter level to patients in depression clinical trails.

Results

The impact of ketamine was drastic with patients responding positively for over two months while lowering the drug dosage each time. The hypothesis is accepted: ketamine is an appropriate drug to treat depression cases that are unresponsive to the usual antidepressants.

Discussion

According to research studies, the symptoms of depression are observed to reduce considerably with ketamine in a very short time in comparison to SSRI that takes roughly longer time to stimulate an effect. When administered via a nasal spray, ketamine prevents NMDA receptors from acting, thus, stopping the excitotoxicity.

Side effects of ketamine

Several side effects are recorded in the clinical trail upon the usage of the drug.

Conclusion                                                          

NMDA receptors use a different mechanism of action to fight depression that is furthermore effective than SSRIs. Ketamine is a successful drug for the treatment of persistent depression in adults by the mode of action of NMDA receptors.

Abstract

The Food and Drug Administration recently recommended ketamine as an antidepressant drug. Depression is a form of mental illness that is common amongst young adults. Traditionally accepted oral antidepressants are proving to be resistant in some depression cases. The drugs do not work at other times even after weeks of administering to a patient. An improved version of ketamine is a drug that is being used to treat resistant depression through the mechanism of action of NMDA receptors. NMDA receptor antagonists (NMDARAs) such as MK -80 and CGP 37849 are proving to have a positive impact in treating depression. The results of antidepressant effects by ketamine can be observed in a matter of hours after use. The drug alters some parts of the brain; patients report almost no symptoms of depression after use. However, the drug has an adverse side effect, and it is up to the medical practitioner to determine if the benefit outweighs the risk to the patient.

Introduction

Background

The prevalence of depression during 21st century has increased at an alarming rate, particularly in younger generations. There are an estimated 350 million people diagnosed with depression worldwide (Lim, Grace Y et al., 2018). Depression is a chronic disease that affects activities of daily life and also confers a 20-fold increase in suicide-related mortality. The affects on productivity are so profound that the cost to the USA economy is estimated to be $36.6 billion annually (Lépine, & Briley, 2011).

The causes of depression could be physiological, deteriorating immune system, increase in stress levels, lack of enough nutrients in the body and parts of the brain recording abnormal activity. However, there is more to depression than just biological causes. Poor diets, the feeling of low self-esteem, sexual and physical abuse are social and psychological factors that have a major impact on the cause of depression.

In recent history, the standard of care for depression has been drugs belong to classes such as SSRI’s, SNRI’s, and TCA’s among others. These agents function by increasing synaptic levels of neurotransmitters either through blocking degradation or reuptake. Recent advances in the understanding of NMDA receptor signaling pathways reveals that this could be an attractive target for the development of novel antidepressants.

There is a clear need for the introduction of novel antidepressants, as presently one-third of patients taking traditional antidepressants report no improvement of their symptoms (Ajubet al., 2018). Ketamine, an NMDARA that originally gained approval in 1970 as a dissociative anesthetic has now expanded its indications to include use in treatment-resistant depression (TDR). Patients that have taken ketamine report improved symptoms within hours of administration. Experts claim that ketamine could be the revolutionary drug in treating depression in this age. Patients have been turning up for treatment in ketamine clinics. The drug has proved to be effective to patients with TDR. Ketamine and analogous compounds offer a novel mechanism of action (MOA) for managing depression. Whereas traditional antidepressants function by enhancing the levels of serotonin, norepinephrine, and dopamine within the synapse, ketamine and other NMDARAs function by blocking the action of glutamine at NMDA receptors.

Rationale                                                                                

Antidepressants are at times unsafe in cases where patients have chronic diseases such as liver, kidney, or heart disease. This is the reason researchers carry out clinical tests and release articles regularly to inform the public about advanced forms of medication that can curb depression effectively. Since ketamine and related compounds work by different mechanisms that may open up treatment options for those who have contraindications to standard therapies.

Objectives

Many types of depression cases are resistant to regular oral antidepressants. The intend of this review is to elaborate on the difference in the MOA that causes NMDARAs to be effective than traditional SSRIs. The FDA in 1970, in the United States, approved a version of the drug ketamine to treat depression. This paper elaborates the effectiveness of the use of ketamine as an NMDARA used in treating resistant depression.

Hypothesis

This paper is about the MOA of NMDARs of ketamine and its s-enantiomer esketamine speed in responding to TRD. NMDARs are effective in treating depression through their MOA as opposed to SSRIs.

NMDARA’s employ a novel mechanism of action for managing depression

The role of an antidepressant is to ensure that chemicals in the brain are balanced. There are types of antidepressants used in treating mental illnesses and depression as well. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) are the most commonly utilized antidepressants. The three most relevant neurotransmitters targeted when considering traditional antidepressants are the monoamine neurotransmitters serotonin, norepinephrine and dopamine. (Dale et al.,2016). These neurotransmitter chemicals have a direct effect on the mood and the emotions of a patient. Although considering the fact a wide range of factors causes depression, it is unusual that this drug only targets the brain to fix depression. Studies claim that depression is, indeed, as a result of chemical imbalance experience in the brain. Traditional antidepressants function by increasing synaptic concentrations of serotonin, norepinephrine and dopamine with serotonin being the one most commonly targeted. However, a deficiency in serotonin does necessarily not cause depression. These could be the reason why many patients report no improvement even after taking these drugs; this is called TDR.

NMDA receptors (NMDARs) regulate glutamate-gated channels that allow for the diffusion of calcium. NMDARs play a vital role in the central nervous system development, the NMDARs located in the hippocampus assist in learning and memory. NMDARs are particularly important as targets in treating diseases associated with the central nervous system. When NMDA receptors are activated in excess, the result is an abundance of calcium influx, which can result in excitotoxicity. Excitotoxicity can lead to the development of neurodegenerative disorders including Alzheimer’s disease and Schizophrenia. Neurodegenerative diseases are managed, in part, by blocking excessive Ca²⁺ influx through utilization of NMDARA’s, which operate as uncompetitive and non-competitive inhibitors of the NMDAR. NMDARA’s currently approved for use or further research in the USA include MK-801, ketamine, amantadine, and memantine.

Pharmacokinetic parameters

One measure of a drug’s affinity and binding-disassociation properties for a receptor is termed its off-rate. Off-rate is measured units of 1/(concentration*sec) and is a measure of the frequency with which the drug disassociates with the receptor. The off-rate of NMDARs is a factor that needs to be considered when assessing a lead compound. Where the off-rate of an NMDARA is very low, the overall drug activity, too, will be low. Low off-rate interferes with the ability of other drug molecules to access the active site (Blanke & VanDongen, 2008). On the contrary, when off-rate is excessively large, disassociation of the NMDARA is rapid, thereby allowing the natural ligand glutamate access to the NMDA receptor. As such, pharmacologists recognize the importance of a moderate off-rate value when developing novel NMDARA’s for depression.

NMDARA’s bind to the NMDA receptor causing a conformational change such that binding of glutamate does not result in the normal physiological response of opening the Ca²⁺ channel. With No Ca²⁺ the inhibitory neuron will hyperpolarize thus, making it too weak to signal a transmission. The most popular theory as to how NMDA receptor antagonism translates to antidepressant activity explains that NMDARA activity on GABAergic interneurons leads to disinhibition of dopaminergic neurons. (Gerhard et al., 2016).

In-Vivo Assessments of NMDARA Antidepressant Efficacy

The forced-swimming test is an assessment used to assess antidepressant activity in rodents. The underlying rationale behind this test is that a less depressed rat will struggle more to avoid drowning, whereas immobility signals despair and a lack of will to survive. The results are as follows: the group of rats given memantine showcased reduced immobility duration as compared to the rats given a saline solution.

Behavioral effects demonstrated by treatment with NMDARAs illustrate the antidepressant efficacy of these agents. A study conducted on mouse models claims that these effects are highly dependent on the fast amalgamation of BDNF. Memantine was administered to rodents at a dose of 20 mg/kg to study the effect that memantine would have on BDNF levels. The rodents that received memantine displayed elevated BDNF levels compared to the control group.

A study that incorporated memantine and imipramine with (R)-enantiomer CGP 40116) was carried out on animals. (Ates-Alagoz & Adejare, 2013). The animals were put under stressors of mild intensity for a long time. This study measured sucrose solution consumption as a surrogate marker of depression levels. The results of this experiment showed a decline in sucrose solution, which was correlated with the depressed state brought upon by the addition of stressors. However, this experiment illustrated, indirectly, that the depressed state was reversible by treatment with the addition of the study drugs. This was evidenced by a return of previous feeding levels in the group given the study drugs.

The above-described in vivo studies illustrate the promising efficacy that NMDARAs as novel antidepressants.

Ketamine

Ketamine, an NMDARA that has seen decades of use as an anesthetic, is now approved for use as an antidepressant. Being an NMDARA, ketamine employs a MOA that is distinct from that of traditional antidepressants (Palucha et al., 2016). This agent is recommended when a patient has failed trials with two different traditional antidepressants. Ketamine enjoys the benefit of having a rapid onset of action. Whereas traditional antidepressants have an onset of action that is measured in weeks, that of ketamine is measured in only several hours. This rapid onset of action displayed by ketamine makes it a particularly valuable treatment option for patients currently experiencing suicidal thoughts (Ajubet al., 2018). Ketamine has the advantage of a much more rapid onset of action than traditional antidepressants. Pharmaceutical preparations of ketamine for use as an antidepressant are optically pure formulations of the S-enantiomer: esketamine. Esketamine is available for use as a nasal spray (SPRAVATO) and as a solution for parenteral use (KETANEST) (Reardon 2018). The prevailing theory regarding the MOA of ketamine as an antidepressant is that through its NMDARA activity on GABAergic interneurons it causes disinhibition of dopaminergic neurons.

Esketamine (SPRAVATO) is an N-methyl D aspartate NMDARA that is used for TDR alongside an oral depressant. The s-isomer of ketamine displays a preferable pharmacodynamic profile compared to the R-isomer.. There are still ongoing developments of intranasal formulation that can effectively treat TRD.

Methods

This is a randomized, twofold visually impaired (neither the specialists nor the members comprehend what treatment the member is accepting), dynamic controlled, multicenter examine (more than 1 think about site) in members with TRD to evaluate the viability, wellbeing, and mediocrity of fixed portions of intranasal esketamine in addition to a recently started oral upper contrasted and a recently started oral stimulant (dynamic comparator) in addition to intranasal fake treatment. The investigation will comprise of 3 stages: Screening/Prospective Observational Phase (4-7 weeks), Double-daze Induction Phase (a month), Follow-up Phase (24-weeks). Members who roll over into a long haul upkeep study won’t take an interest in the Follow-up Phase. Toward the beginning of the screening/imminent observational stage, the member more likely than not had reported non-reaction to somewhere around 1 energizer treatment (in view of Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire [MGH-ATRQ]) in the flow scene of dejection, and member is taking an alternate oral upper treatment on the MGH-ATRQ for at any rate the past about fourteen days at or over the base helpful portion. This upper treatment, just as some other progressing prescriptions being taken for melancholy at screening (counting adjunctive/growth treatments), will proceed from the beginning of Week 1 through the finish of Week 4 of the screening/forthcoming observational stage. Members will be haphazardly appointed to get Intranasal esketamine (56 milligrams [mg]), Intranasal esketamine (84 mg), or Intranasal fake treatment. Likewise, every member will be relegated to get 1 of 4 oral stimulant prescriptions from 2 distinct classes of energizer medications, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine or venlafaxine broadened discharge [XR]), started on Day 1 and proceeded through the twofold visually impaired acceptance stage. Members will be essentially assessed for development in burdensome side effects as evaluated by the change in Montgomery-Asberg Depression Rating Scale (MADRS) all out score at Week 4. Members’ security will be checked all through the investigation.

Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double-Blind Induction Phase-Mixed-Effects Model Using Repeated Measures (MMRM) Analysis [ Time Frame: Baseline up to Day 28 of Double-daze Induction Phase ]

MADRS is clinician-appraised scale intended to gauge discouragement seriousness and to distinguish changes because of upper treatment. Scale comprises of 10 things (evident trouble, revealed bitterness, inward pressure, rest, hunger, focus, stupor, intrigue level, cynical contemplations, and self-destructive considerations), every one of which is scored from 0 (thing is absent or is ordinary) to 6 (serious or constant nearness of manifestations), summed for an absolute conceivable score of 0 to 60. Higher scores speak to progressively extreme condition.

Case Study

To further illustrate the clinical use of ketamine for depression, a published case study will be described here. In 2010, Dr. Scott Irwin and Dr. Alana Iglewicz reported on the care of a patient in a long-term care facility where ketamine was utilized for depression (Irwin & Iglewicz, 2010). The patient (K.H.) presented in this case was a married 70 year-old caucasian male. His past medical history includes a diagnosis of prostate cancer stage IV prostate cancer with metastasis to the bone, lung and liver. K.H. reported a lack of appetite, poor sleep patterns, thoughts of being dead, panic attacks and anxiety. K.H. also described feeling like a burden to his wife who was taking care of him. K.H.’s prescribed medications included methadone 10 mg QID, dexamethasone 4 mg BD, trazodone 50 mg QHS, furosemide PRN, senna PRN, and morphine sulfate 20 mg QH. Upon approval, K.H. was given 32.5 mg of oral ketamine daily. To assess the efficacy of ketamine for alleviating depression in this subject, the authors assessed the percentage change from baseline in HRSD-17 scores. HRSD-17 (Hamilton Rating Scale for Depression) is a clinical assessment used to grade depression severity based on findings in 17 categories. The authors’ presented astounding results indicating that in just 60 minutes after the first dose of ketamine the patient’s HRSD-17 score had dropped 37%. This finding highlights the rapid onset of action ketamine displays for managing depression. Furthermore, the authors found that after 7 days of therapy with ketamine that the HRSD-17 score had dropped by 57% compared to baseline. This case study illustrates that ketamine is powerfully effective for alleviating depression symptoms and has a rapid onset of action.

Primary Source

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