Ketamine’s role in treatment of depression: Study

In continuation of my update on Ketamine

The anaesthetic drug Ketamine has been shown to be beneficial in some cases of depression and suicidal ideation which have typically failed to respond to other standard antidepressant medications. A new study has explored the actual workings of ketamine in depression and found that the drug can act on the same receptors as opioid pain relievers.

The latest study was published in the American Journal of Psychiatry.

For this the researchers from the Stanford’s Neurosciences Institute included 12 volunteers at first. These cases were all of treatment-resistant depression.

The participants were all given infusion of Ketamine. In addition some were administered naltrexone and others normal saline infusion. Naltrexone is a drug that can block the effects of opioids.

Results showed that those on ketamine and saline combination found relief from their depressive symptoms quickly compared to those on ketamine and naltrexone combination. In fact those on ketamine and saline placebo reported at least a 90 percent reduction in their symptoms within the first three days of the infusion.

No such improvement was seen among those on ketamine and naltrexone. This proved that when the opioid actions are blocked, the ketamine cannot function as an antidepressant. Both groups faced certain side effects of ketamine such as an “out-of-the-body” experience, dysphoric feelings, tripping etc. This also showed that the antidepressant action of Ketamine was separate from its usual actions, which were seen in all participants in either group.

The initial trial plan was to include 30 patients. Due to the dramatic improvement seen in one group and no changes in the other, the team decided to stop the trial prematurely. This was to spare patients useless treatment.

Ketamine has been in news recently due to its unexplored potential as an antidepressant. If proven, researchers believe, this could impact depression research significantly. Ketamine has gathered interest mainly because it does not change the brain chemistry unlike other antidepressants. Co-author Boris Heifets, a clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford explained that ketamine blocks the brain’s receptors for glutamate. Glutamate is an important neurotransmitter in the brain. Many researchers have thought that glutamate could be the key zone where ketamine acts as an antidepressant. Heifets added that ketamine is not a simple drug and has varied targets which could be responsible for its antidepressant activities. A lot of money has been spent on developing agents that could work on the glutamate receptors and try to mimic ketamine’s antidepressant actions.

This study shows that the approach is incorrect and glutamates are not the target lead author Nolan Williams explained. Co-senior study author Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford explained that the ketamine was not working as “everyone thought it was working.”

Heifets noted that ketamine is a drug of abuse (called “Special K” in party circuits) that has been in use for a long time and there is an abuse potential of this drug acting on the opioid receptors to provide such effects. He warned that this abuse potential should be kept in mind before ketamine comes into the market as an antidepressant.

However the whole team agrees that this new study shows how ketamine can help patients who have intractable depression. New drugs could be developed in the same lines they explain. These drugs could possibly activate the opioid receptors without having abuse potential they add. Williams added that ketamine has been seen to provide relief of symptoms in other mental ailments such as obsessive compulsive disorders and now is the time to explore if opioids play a role in these diseases as well.

Mark George, a professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina in an editorial accompanying the article wrote that this study is a small one and so should be confirmed in larger trials before conclusions could be drawn.

Ref : https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.18020138

https://en.wikipedia.org/wiki/Ketamine

Study: Ketamine more effective than common sedative in reducing suicidal thoughts

In continuation of my update on ketamine

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine's anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

"There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm," said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. "Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients."

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine's effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

"This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression," said Dr. Grunebaum. "Additional research to evaluate ketamine's antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments."

Study: Ketamine more effective than common sedative in reducing suicidal thoughts

Understanding potential of illicit drug ketamine in treating depression

In continuation of my update on Ketamine 

Advancing the understanding and treatment of psychiatric disorders is
a principal goal of neuroscientists. As mental disorders are the
leading cause of disabilities worldwide, it is concerning that there are
few effective therapeutics on the market due to the lack of knowledge
regarding pathophysiology. In particular, the main treatment for major
depressive disorders are antidepressants, which target the monoaminergic
system and include selective serotonin reuptake inhibitors (SSRIs).
However, these drugs take six weeks on average before symptom relief and
many individuals are unaffected by them.

Ketamine, a synthetic analogue of PCP, has recently taken the
spotlight as a novel, fast-acting antidepressant. The benefits of
ketamine include a one-time, low-dose IV infusion, where symptoms are
alleviated within hours and which lasts for up to two weeks in patients
with depression. Even more compelling is that this regimen affects
patients with treatment-resistant depression, meaning those who do not
respond to current antidepressants. These effects are especially
important in helping individuals with depression who may be experiencing
suicidal ideation because of ketamine's fast-acting nature and it is
the only treatment effective for treatment resistant patients.

However, there are many downsides to the use of ketamine as an
antidepressant, especially with long-term or repeated use. For example,
ketamine is an illicit drug with high abuse potential, commonly known as
the party drug "Special K." Therefore, close clinical monitoring of the
use of this drug is necessary. In regards to neuroscience research in
the past decade, it has been demonstrated that chronic, low-dose
ketamine has been used to study learning and memory deficits in a rodent
model of schizophrenia. The biochemical data from these animals reveal a
change in a specific type of neuron in the brain that is important for
network activity underlying normal cognitive functioning. This begs the
question: Can ketamine work as an antidepressant without producing
cognitive deficits associated long-term use?

In order to address this question, we need to understand the molecular
mechanisms that ketamine is utilizing to produce these beneficial
antidepressant effects. Although researchers do not know exactly how
ketamine works, we know that it is in a different way than current
antidepressants on the market. There is no clear answer yet, but researchers have produced some promising results. Using ketamine to
deepen our understanding of depression will advance the field of neuroscience and ultimately lead to a more effective treatment for the  disorder.

FDA Approves Spravato (esketamine) Nasal Spray for Treatment-Resistant Depression

  In continuation of my update on esketamine

The U.S. Food and Drug Administration   approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression). Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by Spravato administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

"There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment. Because of safey concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient."

Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.

The Spravato labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Because of the risk of sedation and dissociation, patients must be monitored by a health care provider for at least two hours after receiving their Spravato dose. The REMS requires the prescriber and the patient to both sign a Patient Enrollment Form that clearly states that the patient understands they should make arrangements to safely leave the health care setting to get home and that the patient should not drive or use heavy machinery for the rest of the day on which they receved the drug. Additionally, Spravato must be dispensed with a patient Medication Guide that outlines the drug’s uses and risks.

The patient self-administers Spravato nasal spray under the supervision of a health care provider in a certified doctor’s office or clinic, and the spray cannot be taken home. The health care provider will instruct the patient on how to operate the nasal spray device. During and after each use of the nasal spray device, the health care provider will check the patient and determine when the patient is ready to leave.

The efficacy of Spravato was evaluated in three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial. In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depresison and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.

The most common side effects experienced by patients treated with Spravato in the clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.

Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Spravato may impair attention, judgment, thinking, reaction speed and motor skills. Patients should not drive or operate machinery until the next day after a restful sleep. Spravato may cause fetal harm and women of reproductive potential should consider pregnancy planning and prevention; women should not breastfeed while being treated.

Esketamine is the s-enantiomer of ketamine. Ketamine is a mixture of two enantiomers (mirror image molecules). This is the first FDA approval of esketamine for any use. The FDA approved ketamine (Ketalar) in 1970.

Ref  https://en.wikipedia.org/wiki/Esketamine

FDA Approves Spravato (esketamine) Nasal Spray for Treatment-Resistant Depression

CGP3466B compound may effectively treat depression

We know that, Omigapil (TCH346 or CGP3466) is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD). Omigapil was first synthesized at Ciba-Geigy, Basel, Switzerland. Santhera Pharmaceuticals has since taken over production of omigapil and preclinical trials for CMD. In May 2008, omigapil was granted orphan designation to commence clinical trials for. Pharmacokinetic trials are scheduled to commence enrollment in the second half of 2012 to determine the appropriate pharmacokinetic profile of the drug for children with laminin-α2-deficient congenital muscular dystrophy (MDC1A) and collagen VI related myopathy. Santhera Pharmaceuticals will use the phase 1 clinical trial to determine if the drug is safe and acts with the same pharmacokinetic profile in children as it does in adults. The impending clinical trial will take place in the United States at the National Institute of Neurological Disorders and Stroke/National Institute of Health(NNDCS/NINDS) (Bethesda, Maryland) and in the United Kingdom at Great Ormond Street Hospital (UCL

The compound CGP3466B, already proven nontoxic for people, may effectively and rapidly treat depression, according to results of a study in mice. The Johns Hopkins Medicine neuroscientists who conducted the research say that the compound -- previously shown to block cocaine craving in the brains of rodents -- delivers antidepressant effects to mice within hours instead of weeks or months, like currently available antidepressants. The results of the study will be summarized Jan. 12 online in the journal Molecular Psychiatry.

"One of the promising things about CGP3466B is that it targets a new network of proteins," says Solomon Snyder, M.D., professor of neuroscience at the Johns Hopkins University School of Medicine. "That means it may work in patients who are unresponsive to other types of drugs and it lays the foundation for the development of a new class of fast-acting antidepressants that target the same network."

The team's discovery came out of investigations into the workings of a different drug, ketamine, long used primarily at high doses to induce anesthesia during surgery but known, at lower doses, to be a fast-acting antidepressant. Unfortunately, Snyder says, ketamine is addictive and can produce schizophrenialike symptoms, making it unsuitable for prolonged use, but his team hoped it could shed light on how to make a better fast-acting antidepressant.

CGP3466B compound may effectively treat depression: 

A potential new class of fast-acting antidepressant

Scientists from the University of Chicago have discovered that selectively blocking a serotonin receptor subtype induces fast-acting antidepressant effects in mice, indicating a potential new class of therapeutics for depression. The work was published Oct. 29 in Molecular Psychiatry.

Of the subtypes, serotonin 2C receptors stood out. Selectively blocking these receptors in mice significantly reduced depression-like behaviors in only five days, compared to a minimum of two weeks for a control antidepressant medication.

"We observed fast-acting therapeutic effects in multiple behavioral tasks after we administered compounds that selectively block serotonin 2C receptors," said Mark Opal, a graduate student at the University of Chicago and lead author of the paper. "We began our measurements at five days, but we think there's a possibility it could be effective even sooner than that."

Serotonin 2C receptors normally inhibit the release of dopamine, another neurotransmitter commonly associated with mood, from certain neurons. When 2C is blocked, the researchers believe, more dopamine is released into regions of the brain such as the prefrontal cortex. The team also observed the induction of biomarkers that indicate antidepressant action.

This is the first new biological mechanism that has shown the ability to rapidly alleviate symptoms of depression since ketamine and scopolamine, and it potentially represents a much safer alternative. Some current antidepressants on the market already affect serotonin 2C receptors, although not selectively, and Dulawa believes the safety profile is favorable for human use. The team is now investigating compounds suitable for clinical trials.

"One of the primary advantages to our discovery is that this is much more of an innocuous target than others that have been identified," Dulawa said.

A potential new class of fast-acting antidepressant

Compound shown to reduce brain damage caused by anesthesia in early study

An experimental drug prevented learning deficits in young mice exposed repeatedly to anesthesia, according to a study led by researchers from NYU Langone Medical Center and published June 22 in Science Translational Medicine.

The study results may have implications for children who must have several surgeries, and so are exposed repeatedly to general anesthesia. Past studies have linked such exposure to a higher incidence of learning disabilities, attention deficits and hyperactivity.

 CX546

Specifically, the research team found that the experimental drug CX546, part of the AMPAkine class in clinical trials for several neurological conditions, counters for the dampening effect of anesthesia on nerve signaling. The treatment bolstered nerve cell activity as well as learning ability in mice recovering from repeated exposure to general anesthesia.

"Each year, in the United States alone, more than a million children under age four undergo surgical procedures that require anesthesia, and the numbers are growing," says the study's senior investigator Guang Yang, PhD, assistant professor of anesthesiology at NYU Langone. "There are currently no effective treatments to combat potential toxicity linked to repeated anesthesia, and we would like to change that."

Yang's group took advantage of genetically engineered young mice that have protein markers which glow in response to changes in nerve function. Researchers then used advanced microscopy to visualize activity in their brains, comparing nerve signaling activity in those exposed to anesthesia to those who were not.

The research team found that anesthesia exposure resulted in a prolonged reduction of signal transmission among nerve cells following anesthesia. They also observed that CX546 treatment enhances this transmission, along with learning and memory in mice exposed to anesthesia.

The team studied the anesthetic ketamine, which blocks NMDA (N-methyl-D-aspartate) receptor proteins that enable charged particles like calcium to flow into nerve cells, like electric switches that trigger and shape messages. In contrast, CX546 increases nerve cell activity and calcium influx into nerve cells by enhancing the activity of proteins called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors.

"We were able to counter anesthesia-induced deficits in the formation of connections between nerve cells and related learning problems," says Yang. "This work is an important proof-of-principle study, and opens the door to a new direction for preventing long-term neurocognitive deficits."

Ref : http://stm.sciencemag.org/content/8/344/344ra85 

Compound shown to reduce brain damage caused by anesthesia in early study  

New antidepressant acts very rapidly and is long lasting

A first-of-its-kind antidepressant drug discovered by a Northwestern University professor and now tested on adults who have failed other antidepressant therapies has been shown to alleviate symptoms within hours, have good safety and produce positive effects that last for about seven days from a single dose.

The compound, called GLYX-13, (see the structure) is the result of more than two decades of work by Joseph Moskal, research professor of biomedical engineering at Northwestern's McCormick School of Engineering and Applied Science and director of the University's Falk Center for Molecular Therapeutics.

"Our study showed that this compound is capable of eliciting a robust and rapid antidepressant effect without the typical side effects seen with other drugs that also modulate the NMDA receptor," said Moskal, who is founder and chief scientific officer of the Evanston-based biotechnology company Naurex Inc., which conducted the clinical study.

GLYX-13 works by modulating the NMDA (N-methyl-D-aspartate) receptor in the brain, as do current NMDA receptor antagonists such as ketamine, but GLYX-13 does not have their serious and limiting side effects, such as hallucinations and schizophrenia-like effects. (An antagonist is a substance that inhibits the physiological action of another.)

The positive effects of GLYX-13 were evident within 24 hours and lasted an average of seven days. The effect size, a measure of the magnitude of the drug's antidepressant efficacy, at both these times after a single dose was nearly double the effect size seen with most other antidepressant drugs after four to six weeks of repeated dosing.

Side effects of GLYX-13 were mild to moderate and were consistent with those observed in subjects receiving a placebo.

GLYX-13 is a four-amino acid peptide that modulates one of a large family of glutamate receptors, the NMDA (N-methyl-D-aspartate) receptor, in the brain. NMDA receptors play a key role in regulating synaptic plasticity -- the quality of the connection between neurons -- and thus are important in regulating learning and memory functions.

GLYX-13 is administered intravenously. Moskal said Naurex also is working on an oral drug with similar properties and potential.

Moskal hopes that these positive GLYX-13 results and the research efforts of his team and colleagues will help shepherd in more research and grant support for studying the role of the glutamate-mediated processes in neuropsychiatric disorders...

Ref : http://www.nature.com/npp/journal/vaop/naam/abs/npp2012246a.html

New antidepressant acts very rapidly and is long lasting