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New trial shows ketamine’s effectiveness to treat geriatric depression

 

Australian researchers have completed the world’s first randomized control trial (RCT) assessing the efficacy and safety of ketamine as a treatment for depression in elderly patients.

The results, published in the latest American Journal of Geriatric Psychiatry, provide preliminary evidence suggesting ketamine’s effectiveness as an antidepressant when delivered in repeated intravenous doses.

Led by a team of researchers from UNSW Sydney and Black Dog Institute, the trial tested different doses of ketamine amongst 16 older age participants (aged over 60 years) who had treatment-resistant depression, administered at Wesley Hospital.

“These findings take us a big step forward as we begin to fully understand the potential and limitations of ketamine’s antidepressant qualities,” said lead author UNSW Professor Colleen Loo, who is based at Black Dog Institute.

“Not only was ketamine well-tolerated by participants, with none experiencing severe or problematic side effects, but giving the treatment by a simple subcutaneous injection (a small injection under the skin) was also shown to be an acceptable method for administering the drug in a safe and effective way.”

Participants received increasing doses of ketamine over a period of five weeks, with doses optimised for each individual participant using a new dose-titration approach developed by Professor Loo’s Sydney research team and collaborators.

As part of the double-blind, placebo-controlled trial, an active control treatment which causes sedation similar to ketamine, was used to substitute for one of the treatment sessions. Researchers monitored for mood and other side-effects after each treatment session.

Following the RCT, participants also received 12 ketamine treatments in an open-label phase to investigate the effectiveness of multiple doses of ketamine.

By the six-month follow up, 43 percent of participants (7 of 14) who completed the RCT had remitted, with five remitting at amounts below the commonly-used dose of 0.5 mg/kg. Repeated treatments also resulted in a higher likelihood of remission or a longer time to relapse, with an overall response and remission rate of 68.8 percent for the patients receiving ketamine treatment.

“Elderly patients with severe depression face additional barriers when seeking treatment for the condition. Many medications may cause more side effects or have lower efficacy as the brain ages,” said co-author Dr Duncan George from UNSW Sydney. “Older people are also more likely to have co-morbidities like neurodegenerative disorders and chronic pain, which can cause further complications due to ketamine’s reported side effects. “Our results indicate a dose-titration method may be particularly useful for older patients, as the best dose was selected for each individual person to maximize ketamine’s benefits while minimising its adverse side effects.”

Previous studies into ketamine treatments for older people with depression – which are limited to just five case reports – show mixed success, with findings limited by small sample sizes.

More broadly, little is known about ketamine’s potential side effects at different doses, which include cognitive and dissociative effects, elevated blood pressure and heart rate, liver inflammation and urinary problems.

“These results are a promising early piece of the puzzle, but the risks of ketamine use are still not wholly understood. Future studies with greater sample sizes are needed to formally assess ketamine’s side effects, such as its impact on liver function,” Professor Loo added.

The study was a collaboration between UNSW Sydney, Black Dog Institute, Royal North Shore Hospital, The Wesley Hospital Kogarah, the Dementia Collaborative Research Centre and the University of Otago.

Professor Loo will build on these promising results as part of her current work directing the world’s largest trial of ketamine to treat depression, which is now recruiting participants. For more information about the study contact ket.study@unsw.edu.au or call 02 9382 9509.

Also similar related – the use of hallucinogens for treating depression and other issues has developing efficacy – especially psilocybins:

 

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Psilocybin for treatment-resistant depression

 

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Maryland (MD):
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KETAMINE FOR DEPRESSION| BIPOLAR | SUICIDAL THOUGHTS| 703-844-0184| KETAMINE FAIRFAX, VA | 22308 | How can this treatment not be offered to patients?

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Call 703-844-0184 if you are interested in options for Ketamine treatment for Depression, Anxiety, PTSD, fibromyalgia, Lyme disease, CRPS, or other disorders.

NovaKetamine : Ketamine treatments for depression, PTSD, anxiety, pain, and CRPS

 

Ketamine has helped numerous people who have failed so many mainstay therapies. It has treated suicidal thoughts, depression, PTSD, and many other mood disorders in individuals who have gone through multiple standard therapies. How can such an effective therapy not be offered to patients who are failing in standard therapies?

Ketamine For Severe Depression: ‘How Do You Not Offer This Drug To People?’

AUDIE CORNISH, HOST:

Doctors have treated thousands of people suffering from severe depression with ketamine. It’s a hallucinogenic club drug also known as Special K, and it isn’t approved for treating depression. But as NPR’s Jon Hamilton reports, more and more doctors are giving ketamine to patients who’ve run out of other options.

JON HAMILTON, BYLINE: Gerard Sanacora is a psychiatrist at Yale University who has given ketamine to hundreds of patients. As a street drug, ketamine can be dangerous, and for medical purposes, it’s approved only as an anesthetic. So Sanacora says sometimes other doctors tell him…

GERARD SANACORA: This is unethical. How can you be offering this to patients based on a limited amount of information that’s out there and not knowing the potential long-term risk?

HAMILTON: But Sanacora says ketamine often does something no other drug can. It relieves even suicidal depression in a matter of hours.

SANACORA: So if you have patients that are likely to seriously injure themselves or kill themselves within a short period of time and they’ve in fact tried the standard treatments, how do you not offer this treatment to people?

HAMILTON: More and more doctors seem to agree. Dozens of clinics in the U.S. now offer ketamine, and Sanacora says at least 3,000 patients have been treated so far. Early this month, he and other members of a task force from the American Psychiatric Association published a consensus statement on ketamine. It concludes that there is now compelling evidence that ketamine usually work even when other drugs have failed. But there are still lots of questions about ketamine. James Murrough is a psychiatrist at Mount Sinai Hospital in New York.

JAMES MURROUGH: We haven’t had large-scale trials. We don’t know how much or how often it should be given for it to be effective or safe.

HAMILTON: Murrough is an author of another assessment of ketamine that appears in the journal Nature Reviews Drug Discovery. He says there’s an urgent need to answer questions about the drug’s long-term safety because many patients require a dose every couple of weeks to keep depression at bay. Still, Murrough thinks the case for using ketamine is much stronger than it was just a few years ago.

MURROUGH: There’s warranted caution that’s balanced with, you know, an optimism which says we’ve never had a new medication for depression since the era of Prozac.

HAMILTON: Prozac arrived in the 1980s and became the first of a class of depression drugs that target the neurotransmitter serotonin. Ketamine acts on a different neurotransmitter called glutamate. And Murrough says that has got drug firms excited about the possibility of creating a whole new class of drugs for depression.

MURROUGH: Companies are reopening programs. They’re pulling drugs off the shelf that they’ve already developed that they know act on the glutamate system.

HAMILTON: One promising candidate is a chemical sibling of ketamine called esketamine. It’s now in the final phase of testing before consideration by the FDA. Yale psychiatrist Sanacora, who consults for companies developing ketamine-like drugs, says he’s optimistic.

SANACORA: This is probably the most interesting and exciting new development that I’ve seen in my career and probably going back over the past 50, 60 years.

 

 

Ketamine for Depression| Bipolar | Suicidal thoughts| 703-844-0184| Ketamine Fairfax, Va | 22308 | Ketamine Can Rapidly reverse depression and suicidal symptoms |

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Call 703-844-0184 if you are interested in options for Ketamine treatment for Depression, Anxiety, PTSD, fibromyalgia, Lyme disease, CRPS, or other disorders.

 

The articles below link to research and mainstream media demonstrating the efficacy of Ketamine infusions and intranasal Ketamine approaches for depression. The IV formulation is very effective for immediate relief of depression and even suicidality. The effects are almost immediate in some of our cases.

 

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Ketamine Relieves Depression By Restoring Brain Connections

Chris Stephens, 28, has been battling depression all of his life. At times he wouldn’t get out of bed for weeks. In January, he said his depression hadn’t returned since he started taking ketamine.

Lianne Milton/For NPR

Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.

Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.

The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.

“It’s exciting,” says Ron Duman, a a psychiatarist and neurobiologist at Yale University. “The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression.”

Ketamine is an FDA-approved anesthetic. It’s also a popular club drug that can produce out-of-body experiences. Not exactly the resume you’d expect for a depression drug.

But a few years ago, researchers discovered that ketamine could help people with major depression who hadn’t responded to other treatments. What’s more, the relief came almost instantly.

The discovery “represents maybe one of the biggest findings in the field over the last 50 years,” Duman says.

A rat neuron before (top) and after (bottom) ketamine treatment. The increased number of orange nodes are restored connections in the rat’s brain.

Ronald Duman/Yale University

Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.

The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to “rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress,” Duman says.

A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.

It’s possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. “What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”

And there’s also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.

His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.

Preliminary results suggest that “some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine,” Zarate says.

One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

From Chaos To Calm: A Life Changed By Ketamine

 

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

 2018 Jan 1;225:545-551. doi: 10.1016/j.jad.2017.08.081. Epub 2017 Aug 30.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Abstract

OBJECTIVES:

Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author.

METHODS:

As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration.

RESULTS:

Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were “much” to “very much” improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration.

LIMITATIONS:

Retrospective review from a single practice without placebo control with potential for response and recall bias.

CONCLUSIONS:

InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted.

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Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. <<< ARTICLE link

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

Ketamine Fairfax, Va 22308 | Ketamine for Depression | Dr. Sendi |703-844-0184 | Depression Makes you age faster – consider Ketamine therapy for rapid anti-depressant actions

 

NovaKetamine : Ketamine treatments for depression, PTSD, anxiety, pain, and CRPS

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Could Depression Make You Age Faster? Mental Illness Could Accelerate Cellular Aging

As if major depressive disorder (MDD) didn’t already give people enough cause to abandon their sense of optimism, a new study into cellular aging has found links between depression and a greater risk for aging-related diseases, such as heart disease, diabetes, obesity, and cancer, suggesting to researchers that forms of depression could underlie cellular aging.

Cellular aging takes place as a result of several factors, but one of the more popular theories of aging deals with shortening telomeres. Think of telomeres as the plastic tips on the ends of shoelaces, but for chromosomes. Telomeres prevent the chromosome’s frayed ends from fusing together and tarnishing the cell’s blueprint. When a cell divides, the telomeres necessarily shorten in order to make up for the DNA that was lost in duplication. Scientists measure telomere length in base pairs — essentially DNA building blocks — with newborns having roughly 8,000 base pairs compared to a 65-year-old’s 1,500 base pairs.

According to the present study, published in Molecular Psychiatry, people suffering from MDD had significantly fewer base pairs than non-sufferers. Worse, the severity and duration of a person’s depression correlated highly with having shorter telomeres, even after researchers controlled for lifestyle factors, such as smoking, alcohol consumption, weight, and other factors known to accelerate cellular aging.

While major depressive disorder (MDD) is commonly known for its affective symptomatology, the disorder is increasingly recognized for the association with impaired somatic health. Depressed individuals evidently show an increased risk of developing various aging-related somatic diseases, such as coronary heart disease,1 type 2 diabetes,2 obesity,3 dementia4 and cancer.5 Moreover, MDD enhances subsequent decline in physical6 and cognitive functioning4 and increases the overall mortality risk.7, 8 These associations may partly be explained by unhealthy lifestyle behaviors among the depressed, such as smoking, alcohol use and physical inactivity. However, several studies have found independent effects of depression,2, 3, 7 which suggests that underlying biological processes are involved as well.

The increase in aging-related somatic conditions has been hypothesized to be a consequence of accelerated biological aging in the depressed population (for example, Wolkowitz et al.9, 10). This process is thought to occur at the cellular level, more specifically, at the level of telomeres. Telomeres are specialized nucleic acid–protein complexes that cap the ends of linear DNA and protect DNA from damage. Due to the ‘end-replication problem’, the final part of the telomere fails to be replicated during every cell division, causing telomeres to become progressively shorter. When telomeres reach a critically short length, cells become susceptible to senescence or apoptosis.11 Dysregulation of immune and metabolic stress systems might contribute to telomere shortening by increasing the oxidative stress, which in turn damages the telomeres.9, 12 In contrast, telomere shortening can be counteracted by telomerase, a ribonucleoprotein enzyme that elongates telomeres by adding nucleotides to the end of chromosomes.13, 14 Shorter telomere length (TL) has been linked to the development of various aging-related diseases such as cardiovascular disease,15 obesity,16 diabetes,17 cancer18 and cognitive decline,19 as well as to earlier mortality.20

Recently, some studies have associated shortened telomeres with MDD.21, 22, 23, 24, 25, 26 Simon et al.21 were the first to find such an association: they found that 15 MDD and 29 bipolar patients had shorter TL compared with 44 non-depressed subjects. This association was replicated by Lung et al.22 and Hartmann et al.,23 but only partially by Wolkowitz et al.25 Also, in somatically diseased patients24 and in an older sample,26 MDD was found to be linked to shorter TL. Suggesting a ‘dose–response’ association, Wolkowitz et al.25 found that TL was inversely correlated with lifetime depression duration, but two other studies could not confirm this link for chronicity or severity.23, 26 All prior studies, however, involved a specific somatic sample,24 an older sample24, 26 or a small study sample (n<100)21, 23, 25, 26 that did not allow to fully control for influential confounders such as smoking, alcohol use, BMI and physical activity. Consequently, prior study findings have an unknown generalizability to the population of adults with current or remitted MDD. Considering the conflicting results and limitations discussed above, it remains unclear whether MDD patients indeed show a pattern of accelerated biological aging that might account for the decreased somatic health observed in this patient group.

As a consideration for treatment, why not try to rapidly reverse your depression by using Ketamine or TMS?

 

Effects of a ketamine metabolite on synaptic NMDAR function

So why treat Depression? Because it makes you age faster!! Use Ketamine treatments to get that done quickly:

Depressed
703-844-0184 |Ketamine for depression, CRPS, PTSD | Alexandria, Va |22308

As if major depressive disorder (MDD) didn’t already give people enough cause to abandon their sense of optimism, a new study into cellular aging has found links between depression and a greater risk for aging-related diseases, such as heart disease, diabetes, obesity, and cancer, suggesting to researchers that forms of depression could underlie cellular aging.

Cellular aging takes place as a result of several factors, but one of the more popular theories of aging deals with shortening telomeres. Think of telomeres as the plastic tips on the ends of shoelaces, but for chromosomes. Telomeres prevent the chromosome’s frayed ends from fusing together and tarnishing the cell’s blueprint. When a cell divides, the telomeres necessarily shorten in order to make up for the DNA that was lost in duplication. Scientists measure telomere length in base pairs — essentially DNA building blocks — with newborns having roughly 8,000 base pairs compared to a 65-year-old’s 1,500 base pairs.

According to the present study, published in Molecular Psychiatry, people suffering from MDD had significantly fewer base pairs than non-sufferers. Worse, the severity and duration of a person’s depression correlated highly with having shorter telomeres, even after researchers controlled for lifestyle factors, such as smoking, alcohol consumption, weight, and other factors known to accelerate cellular aging.

“Psychological distress, as experienced by depressed persons, has a large, detrimental impact on the ‘wear and tear’ of a person’s body, resulting in accelerated biological aging,” study author Josine Verhoeven, a researcher at the Free University in Amsterdam, told Live Science. Verhoeven and her team observed that many of these physical ailments also arise most often as people age, encouraging them that “the findings might help explain the variety of health complaints often experienced by people with major depression.”

In pure numbers, the almost 1,900 depressed subjects had fewer base pairs than their 500 non-depressed cohorts. Healthy participants’ telomeres were, on average, 5,540-base pairs long. Meanwhile, the depressed subjects’ telomeres were 5,460-base pairs long. Individuals ranged in age from 18 to 65, and corroborating prior studies into telomere-shortening, the number of base pairs reduced with each year of age, by an average of 14 pairs per year.

How To Treat Shrinking Telomeres

All hope is not lost for depression sufferers, nor those who are quickly approaching their 1,500-base pair checkpoint. Even though a person’s cells will divide roughly 50 to 70 times over the course of his or her life, at which point the cells either die or become so genetically damaged they lead to cancer, there is an enzyme called telomerase that may reverse the cellular aging process. “In young cells, telomerase keeps telomeres from wearing down too much,” wrote University of Utah science news specialist, Lee J. Siegel. “But as cells divide repeatedly, there is not enough telomerase, so the telomeres grow shorter and the cells age.”

However, scientists believe the enzyme may be able to elongate telomeres through certain lifestyle changes. “A healthy lifestyle, such as enough physical exercise, not smoking, and a healthy diet,” Verhoeven said, “might be of even greater importance in depressed individuals than it is in the non-depressed.” What remains uncertain is whether active lifestyle changes would be contributing directly to telomere lengthening, which thereby reduces a person’s risk for depression; or whether the increased exercise, not smoking, and healthy diet bypass the telomeres — which are shortening independently — and affect depression on their own.

Part of the challenge in teasing out the underlying factors is that depression arises from a mixture of genetic, biological, environmental, and psychological factors. The disorder isn’t simply a case of the blues. It’s an illness — a chemical imbalance that requires treatment through anti-depressants targeting specific neurotransmitters, such as serotonin and norepinephrine. While scientists have come to a consensus about these chemicals, like many aspects of the brain, the specific mechanisms remain a mystery.

According to Etienne Sibellie, an associate professor of psychiatry at the University of Pittsburgh, the present study succeeds in its robust analysis. And despite a seemingly marginal decrease of 80 base pairs across both groups, Sibellie argues the “small effect” is still “real.” In terms of an active lifestyle change, he told Health Day, “it’s just not known whether it has an impact on cell function.”

“If that’s the case,” he said, “it has potential therapeutic importance.”

Source: Verhoeven J, Revesz D, Epel E. Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Molecular Psychiatry. 2013.

Major depressive disorder and accelerated cellular aging

 

 

 

Bleeding to Death from Synthetic Marijuana

Adulterants in drugs are commonly found, such as Levamisole in cocaine. Now, there are reported outbreaks of people bleeding to death from synthetic marijuana. The Virginia Department of Health released a flyer regarding this issue today:
Coagulopathy in Emergency Department Patients Reporting Synthetic Cannabinoid Use April 5, 2018 Dear Colleague: The Virginia Department of Health recently received a report of a case of elevated prothrombin time international normalized ratio (INR) in a patient who reported use of synthetic cannabinoids. Currently, the Illinois Department of Public Health (IDPH) is investigating an outbreak of Vitamin K-dependent coagulopathy among emergency department (ED) patients reporting synthetic cannabinoid use before suffering severe bleeding. As of April 4, 2018, IDPH has received reports of 81 cases, including two deaths. I am writing to alert you as there is a potential for additional cases in Virginia. Patients with Vitamin K-dependent coagulopathy may first present to the ED with bleeding from at least one site, before returning later with an extremely elevated INR and severe bleeding requiring hospital admission. As ED and urgent care providers are likely to be the first healthcare providers to encounter these patients, we encourage you to implement the following guidance for patients who present with bleeding not from an injury and not otherwise explained, including epistaxis, bleeding of the gums, bruising, hematemesis, hematuria, hematochezia, menorrhagia: 1. Ask patients if they have used synthetic cannabinoids within the last 3 months. Terms for these products include K2, spice, synthetic marijuana, fake weed/legal weed, and genie. 2. If the patient reports synthetic cannabinoid use or you suspect use, check the patient’s INR before releasing them. 3. If you encounter a patient with significant bleeding and an elevated INR without a definitive etiology (e.g. taking warfarin or overdose of rat poison), please promptly report the case to your poison center at 1 (800) 222-1222. 4. If you have previously encountered any similar cases since February 1, 2018, please also promptly report the case to your poison center at 1 (800) 222-1222. For questions regarding the treatment and management of these patients, please contact your poison center, 24/7 at 1 (800) 222-1222. For additional information on the public health response, please contact your local health department. Sincerely, Marissa J. Levine, MD, MPH, FAAFP State Health Commissioner A version of this letter is available on the VDH Resources for Health Care Professionals web page.

703-844-0184 | KETAMINE INFUSIONS |KETAMINE for DEPRESSION | KETAMINE – ENJOY LIFE, DON’T JUST WALK THROUGH LIFE | KETAMINE DOCTORS IN VIRGINIA | FAIRFAX KETAMINE | 703-844-0184 | KETAMINE AND DEPRESSION TREATMENT – Newsweek Article | 22308 |22305 | 22304 | 22191 |22192 |22193 | 20118 | 20104 | KETAMINE TREATMENT FOR DEPRESSION CBS News – Ketamine for Suicidal ideation |CRPS |RSD |KETAMINE INFUSIONS FOR PAIN | SPRINGFIELD , VA KETAMINE |

CAll 703-844-0184 for an immediate appointment!

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com

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Below is the latest on CBS for Ketmine treatment for Depression. Don’t Just walk through life..enjoy it.

Ketamine has been very successful in treating depression and suicidality in many patients over a long period of time:

Image result for suicidal person
703-844-0184 | Ketamine for Depression | Virginia |Fairfax | Loudon | Alexandria Ketamine infusions | PTSD | Anxiety

Ketamine gaining popularity as a treatment for the severely depressed

Anne Stallings says she has been battling severe depression for most of her life. She tried anti-depressants and even electroconvulsive therapy, but nothing worked until she went to a Ketamine  clinic  and tried ketamine, reports CBS News correspondent Paula Reid. 
 
“It was like the fifth treatment in and I had come home from the grocery store and I was putting away the groceries and I was like, ‘Wow, this is how you don’t feel depressed.’ It was like from turning on a black and white TV to a color TV,” Stallings said.   
 
Ketamine was approved by the FDA in the 1970s to sedate patients during medical procedures. It is more commonly known as an animal tranquilizer and in powder form as “Special K,” a club drug used to get high.
 
Today, ketamine is being provided legally off-label to treat depression at an estimated 250 clinics across the U.S.

ctm-saturday-clean-feed-20180203-cr470c-0700-0900-01-frame-72699.jpg

Anne Stallings

 CBS NEWS

Dr. Steve Levine offers intravenous ketamine infusions at several clinics around the country as an alternative to common anti-depressants. He says he treats about 70-80 patients across all the offices on any given day.

“Everything for the past 50 years has been based on the chemical imbalance theory of depression which has never held water,” Levine said. “So all these medicines, while they do help a lot of people, are based upon a flawed theory. And that is probably one of the reasons why they do take so long to work. They all take weeks to months to work so here is a medicine that people can take infrequently that is based upon a theory of the brain that makes a lot more sense and it works almost immediately.”
 
Stallings didn’t have time to wait. She had an especially hard time over the holidays and when her father got sick, she thought about taking her own life.
 
“I actually had suicidal ideations and the one thing about ketamine was that I was able to get in here emergently because I knew what was going on and when I left here my suicidal thoughts were gone,” Stallings said. 
 
That is in line with what Columbia University discovered in one of the largest studies yet on ketamine. Researchers found the drug was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients. The effects lasted up to six weeks.
 
Twenty-two-year-old Marc Nelson ditched his antidepressants for ketamine and talk therapy. He says he now feels more like himself, but it came at a cost. He has spent more than $10,000 on treatments.
 
“So many different drugs that I am now off of all of them, which you know, the side effects were just not tolerable to me. They make me a zombie. I was not happy,” Nelson said. 
 
But these infusions can have their own pitfalls. Ketamine can cause people to feel detached from their bodies.

ctm-saturday-clean-feed-20180203-cr470c-0700-0900-01-frame-74486.jpg

Marc Nelson receives a ketamine treatment 

 CBS NEWS

“The 45-minute period of very floatiness, I sometimes get nauseous,” Nelson said. “It’s a very interesting process. … I just lost my train of thought.”
 
Once the treatment was finished, Nelson said he felt “clear, cognizant” and “definitely able to pronounce” his words again.
 
Asked to address critics who say he’s making money by giving people the opportunity to get high, Levine said, “I would say that if you ask any of our patients none of them feel that they are getting high.”

“People tend to focus on the party use of ketamine, because it is more exciting, it’s sexier in some way. It does it a disservice because that’s a very small fraction of its use,” Levine added. “And as far as the money making aspect of this, if you were doing things in the right way you’re not gonna make a lot of money.”

Ketamine has piqued the interest of some major pharmaceutical companies. There are half a dozen drugs in development that mimic the way ketamine works, with some undergoing FDA clinical trials for approval as antidepressants.

For decades, Dr. Gerry Sanacora has been studying ketamine at Yale.

“What we’re trying to understand is what does it change in the brain that allows that sustained anti-depressant like response?” Sanacora said. 
 
He says the drug is not addictive in the way opioids are, but could still be harmful in the long run.
 
“There is at least evidence in animal models that these type of medications can actually cause some structural damage in the brain. That’s usually at higher doses, that’s usually at longer term exposure but we don’t know where that level is,” Sanacora said. 
 
Dr. Levine said he monitors patients closely. 

“In our population even people who have been having ketamine on a maintenance basis for up to six years now we haven’t seen any sign of that,” Levine said.

But for Anne Stallings, despite the unknowns, she’s content with a chance to feel normal.
 
“If I can live a quality, happy life, and be productive, be able to go to work, to be able to have my family, to enjoy life – not walk through life but enjoy life – then it’s worth it.”

Ketamine for rapid reduction of suicidal thoughts 2017  <article out of Colombia University

In major depression with clinically significant suicidal ideation,
a single subanesthetic ketamine infusion, adjunctive to ongoing
pharmacotherapy, was associated with a greater reduction
in suicidal thoughts at day 1, the primary outcome measure,
compared with midazolam control infusion. The adjusted
mean difference of 4.96 points on the clinician-rated SSI, a
Cohen’s d of 0.75, and a number needed to treat of 4 for
response represent a medium-sized effect. Adverse effects—
mainly blood pressure increase and dissociative symptoms—
were similar to those reported in other ketamine studies (37)
and were mostly mild to moderate, and transient, typically
resolving within minutes to hours after infusion. Improvement
in suicidal ideation largely persisted during the 6-week period of uncontrolled observation, during which
standard pharmacological treatments were also optimized.
To our knowledge, there is no established definition of a
clinically meaningful reduction in score on a standard suicidal
ideation scale. A prospective study (N=6,891) of patients
with depressive disorders (23) found that a baseline SSI
score .2 predicted suicide during up to 20 years of follow-up.
In a prospective study of 562 inpatients (64% with a mood
disorder) who endorsed suicidal thoughts (38), those who
experienced a 50% reduction within 24 hours from a severe
level (suicidal ideation “most of the time”) had one-third the
risk of subsequent self-harm events during a mean length of
stay of 24 days, compared with those whose suicidal thoughts
remained elevated. Given concerns about ketamine’s 1- to 2-week antidepressant
effect in previous studies (11), it is notable that the
improvement in suicidal ideation in this trial was largely
maintained through the 6-week follow-up ratings. This may
be partly explained by the fact that patients continued prior
psychotropic medication, which was optimized after completion
of day 1 postinfusion ratings. Our result is consistent
with the Hu et al. trial (41), in which patients with major depression
who were randomly assigned to receive a single
ketamineinfusion onday 1 of escitalopram therapy experienced
a faster response compared with patients who received a saline
control infusion, and the benefits were maintained for 4 weeks.

We found greater reductions in overall mood disturbance,
depression, and fatigue, assessed with the POMS, on day 1 after
ketamine compared with midazolam.A
secondary analysis of adjunctive ketamine (N=14) found
a reduction in suicidal ideation even when depression did
not remit (17)Ketamine is mechanistically distinct from
currently approved antidepressants, its therapeutic effects
possiblyinvolving rapid synapse formation (44)

Montgomery-Asberg Depression Rating Scale

In summary, in this randomized trial in suicidal depressed
patients, a single adjunctive subanesthetic ketamine infusion
was associated with a clinically significant reduction
in suicidal ideation at day 1 that was greater than with the
midazolam control infusion. In the context of standard, optimized
treatment after the ketamine infusion, this improvement
appeared to persist for at least 6 weeks. The
clinical applicability of our findings was improved with infusion
administration by a psychiatrist and without a medication
washout, as has been done in some studies

Profile of mood states

_Modified_Scale_for_Suicidal_Ideation

Image result for suicidal person
703-844-0184 | KETAMINE INFUSIONS |KETAMINE for DEPRESSION | KETAMINE – ENJOY LIFE, DON’T JUST WALK THROUGH LIFE | KETAMINE DOCTORS IN VIRGINIA | FAIRFAX KETAMINE | 703-844-0184 | KETAMINE AND DEPRESSION TREATMENT – Newsweek Article | 22308 |22305 | 22304 | 22191 |22192 |22193 | 20118 | 20104 | KETAMINE TREATMENT FOR DEPRESSION CBS News – Ketamine for Suicidal ideation |CRPS |RSD |KETAMINE INFUSIONS FOR PAIN | SPRINGFIELD , VA KETAMINE |

 

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NOVA Health Recovery  <<< Ketamine infusion center in Alexandria, Virginia 703-844-0184  – consider ketamine for addiction treatment

CAll 703-844-0184 for an immediate appointment!

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com

Ketamine center in Fairfax, Virginia    << Ketamine infusions

NOVA Health Recovery – KETAMINE SYSTEMS<< Link

 

Interesting New article in Newskeek this month regarding a new study demonstrating the efficacy of Ketamine for the treatment of depression:

 

PARTY DRUG KETAMINE FOUND TO RELIEVE DEPRESSION AND HELP CONTROL EMOTIONS

Ketamine could offer a fast and effective treatment for people with depression, even those who have failed to respond to current therapy options. A new medical reviewpublished this month adds to the growing evidence that the drug could be used in a clinical setting.

The review, published in the Harvard Review of Psychiatry, analyzed 47 studies on ketamine as a treatment for depression. The paper outlined specific ways in which ketamine affected the brains of depression patients.

Ketamine is a drug that can relieve pain and cause feelings of relaxation. It is generally used as an anesthetic in medical setting, but it is also abused as a party drug. Recreational users typically seek a sensation described as being similar to an out-of-body experience.

A New Drug for Depression

03_05_ketamine
Ketamine for depression |703-844-0184 | Fairfax Virginia |22308 | 22304 |

 

Despite its popularity at parties, ketamine has been the subject of numerous clinical studies for its potential to treat depression. Data have been mounting in its favor, and now a team at Harvard Medical School has reviewed the evidence thus far.

The authors found that many patients given ketamine displayed measurable positive changes in brain activity in areas associated with the ability to process and control emotions, Business Insider reported.

Those changes include activation of the subgenual anterior cingulate cortex—connected to both emotions and cognition—as observed by neuroimaging. The activation was directly associated with improvement of depression symptoms in as little as 24 hours after patients received a single intravenous subanesthetic ketamine dose.

The drug also enhanced how the brain responded to positive emotions, a change indicated by increased connectivity in the right-hemisphere caudate. That enhancement helped relieve symptoms of depression, possibly because of this region’s connection to the brain’s reward system.

Related: Perfectionists Are More Likely to Be Depressed—But One Thing Might Help Them

Ketamine also appears to decrease the ability to self-monitor, the report noted. This decrease may cause “emotional blunting,” which could help increase reward processing—and, in turn, happiness.

How Does Ketamine Work? 

Although the review did not describe exactly how ketamine produces its antidepressant effect, the authors noted that the effect may be indirect. Past research found that ketamine affects several receptors in the brain, such as opioid receptors, adrenegic receptors and serotinin receptors. The review concluded that the side effects of ketamine’s effect on those receptors may be the root cause of its antidepressant response. However, more research is needed to confirm this.

Related: Are Nice People More Likely to Be Depressed?

The recent review is the latest scientific publication to suggest that this commonly used (and abused) drug could be an extremely helpful depression treatment.

Depression is a mental health condition characterized by prolonged feelings of extreme sadness and anxiety. According to the Center for Disease Control and Prevention, about one in every six adults will deal with depression at some point in their lives.

Though the results sound exciting, ketamine is not without its side effects. For example, an estimated 40 percent of users will experience some type of short-term effect of ketamine when administered in a hospital setting: It could be delirium, dizziness, hallucinations, nightmares or nausea and vomiting. There is currently no long-term need for ketamine use, but those who abuse the drug by taking it chronically may actually experience increased depression, or have memory and vision problems.

Although there are a number of treatments for this condition, not everyone is responsive to them. Ketamine may offer a useful alternative, but more research is necessary in order to better understand how ketamine affects depression patients before it is widely used for that purpose.

Business Week Article March 8 for Ketamine

  • Ketamine is emerging as a potential new treatment for some types of depression.
  • A new review published in the Harvard Review of Psychiatry outlines the promise and limitations of existing ketamine research.
  • Some researchers have called the drug “the most important discovery in half a century.”
  • It’s been called “the most important discovery in half a century,” and for some of the people who have tried ketamine, it may feel that way too.

    The compound has a reputation as a party drug, but ketamine is increasingly being studied for its potential use as a rapid-fire treatment for depression. In people who live with the disease, thoughts of suicide can strike suddenly and without warning. Fast-acting, successful interventions are hard to come by.

    But a spate of recent research suggests that ketamine could provide quick and powerful relief — even to people whose depression has repeatedly failed to respond to other medications and to those who are suicidal.

    Experts say they’re onto something promising. In a field that hasn’t seen a new class of drugs in nearly four decades and in which patients are often desperate and suicidal, that kind of sentiment holds a lot of weight.

    “Imagine arriving in the emergency room with severe pain from a kidney stone — pain so bad that you can’t think. You’ll do anything to make it go away. And the doctors say, ‘here’s a drug that we’ve been using for 30 years, it works 50-60% of the time, and it should start to work in 4-6 weeks'” Cristina Cusin, a psychiatrist at Massachusetts General Hospital and an assistant professor at Harvard University, told Business Insider. “That’s currently the best we can do” for someone who is suicidal.

    Cusin co-authored a large new review of the existing research on ketamine that was published this month in the Harvard Review of Psychiatry. Her findings shed light on the need for new treatments, but she also advises caution for patients.

    “We are just scratching the surface of the mechanisms of action with ketamine,” Cusin said.

    Trying to tackle a uniquely troubling problem

    alone man oceanShutterstock

    For her review, Cusin looked at almost 40 ketamine studies that involved brain imaging.

    Cusin faced challenges in assembling very different studies into one review, but she came up with some key takeaways. For one, she observed that people given ketamine experience measurable brain changes — many of them in areas that have been tied to our ability to process and regulate emotions.

    Ketamine also appeared to increase activity in parts of the brain linked with reward processing, which would help to explain some of its antidepressant effects.

    Nine out of 10 people who die by suicide have a mental illness at the time of their deaths, according to the American Foundation for Suicide Prevention (AFSP). But current interventions for those who find themselves contemplating suicide are limited to hotlines, sedative drugs, and talk therapy.

    Rates of suicide in the US have risen steadily over the past few years, with roughly 123 people dying this way per day, according to the AFSP. Men die by suicide 3.5 times more often than women.

    The reasons behind this rise are complex, but two of the biggest problems are a lack of access to mental health care and the stigma that continues to shroud mental illness.

    “If you have asthma, it’s not considered your fault. But somehow if part of your brain isn’t functioning, it’s your fault,” Cusin said. “It’s a residual leftover from more ignorant times.”

    It’s easy to see why the prospect of a new approach would inspire hope.

    The promise of a new drug

    Physicians and psychiatrists have been doling out the same drugs to people with depression for decades. But research suggests that while antidepressants can work wonders for some people, they don’t help everyone. The medications also come with a range of unpleasant side effects that can include weight gain, less interest in sex, anxiety, and insomnia.

    Like Cusin, most scientists who work in the space think it’s time for a new tactic.

    iv drip bagShutterstock

    Some of them have found hope in recent months in psychedelic drugs like ayahuasca and magic mushrooms — which appear to reduce depressive symptoms by increasing the connectivity among previously segregated parts of the brain. But those drugs are widely illegal, and many people aren’t interested in having a full-blown psychedelic experience.

    Several recent studies published over the past few months suggest that ketamine could be the alternative drug people are looking for, since it is legal and also appears to work quickly.

    Last December, researchers at Columbia University Medical Center who were working with depressed and suicidal patients found that ketamine worked significantly better at curbing their suicidal thoughts than a commonly used sedative. Most participants in the study saw their moods began to lift within 24 hours. In some people, those effects lasted more than a month.

    The authors of a 2012 review of four preliminary studies on ketamine in patients with severe depression expressed surprise at how rapidly the drug appeared to produce positive, precise results.

    “The findings were unanticipated, especially the robustness and rapidity of benefit,” the authors wrote in their paper. “Ketamine appeared to directly target core depressive symptoms such as sad mood, suicidality, helplessness and worthlessness, rather than inducing a nonspecific mood-elevating effect.”

    The researchers behind another 2012 study on the drug went called ketamine “the most important discovery in half a century.”

    Ketamine’s promise has not gone unnoticed among pharmaceutical companies. Johnson and Johnson is developing a form of ketamine that could be better tolerated and would be marketed as an antidepressant. And Allergan is in the last phase of clinical trials with a drug that acts on the same receptor as ketamine.

    However, Cusin believes we need more research.

    The biggest unanswered question: long-term effects

    Some people with depression are opting to pay for pricey treatments at a range of clinics currently offering the drug — if they can afford it. Treatments can cost between $400 and $1,000 per infusion, and most clinics recommend that patients receive more than one ketamine infusion to get the maximum benefit.

    However, the Food and Drug Administration has not approved the existing drug or any new formulation of it to treat depression. Using ketamine as an antidepressant is therefore considered “off-label,” which means it is up to health insurance providers to decide whether to offer patients any reimbursement.

    ketamineAP Photo/Victoria Arocho

    Plus, like any drug, ketamine has risks and side effects; some studies suggest that could include blood pressure complications. Most importantly, we don’t have many studies that tell us what happens in the long term after a ketamine infusion. Most existing ketamine and depression studies have been limited to several weeks, so it remains unclear how long the benefits last and what the long-term effects may be.

    Because of these complications and unanswered questions, many people wanting to try ketamine for depression are left in a sort of limbo.

    But Cusin believes the drug “absolutely has potential.”

    “In the next few years I’m really hopeful that we’re going to see new drugs that are completely different than what we have now,” she said.

     2018 Feb 20. doi: 10.1097/HRP.0000000000000179. [Epub ahead of print]

    Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature.

    Abstract

    Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine’s mechanism may be elucidated in humans. Here, we review 47 articles of ketamine’s effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, may increase emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine’s mechanism of antidepressant action.

    Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.

    In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).

    The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen’s d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.

    Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.

  • Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.

    This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).

    The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.

    Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.

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Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it’s powerful antidepressant properties (Berman et al 2000Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it’s beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism
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Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).

 2013;34(4):287-93.

Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression.

Abstract

OBJECTIVES:

Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.

METHODS:

In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.

RESULTS:

Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.

CONCLUSION:

The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Lithium’s Emerging Role in the Treatment of refractory major depression episodes – augmentation of antidepressants

Subanesthetic ketamine decreases the incentive-motivational value of reward-related cues.

The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers.

Signaling Pathways Underlying the Rapid Antidepressant Actions of Ketamine

 

Cognitive disorders: the role of dendritic spines.

Cognitive disorders: the role of dendritic spines.

www.paulmorrison.org/cognitive-disorders-the-role-of-dendritic-spines/

Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be ‘absorbed’ back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are ‘pruned’ back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer’s and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.

REGULATION OF THE SPINE:

The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHOfamily. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to ‘coalesce’ at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it’s complexity (and beauty).

Glutamate & GABA for psychiatrists

Rapid Dissemination of Information
Glutamate and GABA are the archetypal ‘fast’ transmitters. If a neuron in the brain ‘wishes’ to communicate rapidly with another cell, the chances are that it will utilise glutamate or GABA. Of course, glutamate neurons exert an excitatory influence on the cells they contact, whereas GABA, at least on first glance, is inhibitory.

Fast transmitters bind to receptors on membrane-spanning ion channels. An ion-channel is in constant flux between various conformations: e.g. open, closed, desensitised. Binding of fast transmitter ‘causes’ the ion channel to snap open for brief periods, and ions rush down their concentration gradients causing an abrupt, short-lived, change in the local membrane potential of the post-synaptic cell (Figure 1). From start to finish the whole process is over within tens of milliseconds, and constitutes a discrete electrical signal (termed an excitatory or inhibitory post-synaptic potential; EPSP, IPSP).

nmda receptor

Figure 1. The NMDA Receptor mediates an EPSP.

Neurotransmission v neuromodulation
Fast transmission, as a concept, pre-supposes slow transmission. The classical slow transmitters are the monoamines, e.g. noradrenaline and dopamine. These substances are used as transmitters by neurons within specific brainstem nuclei, whose axons project to numerous subcortical structures and large areas of cortex. There are relatively few monoamine neurons (tens of thousands), but their projections show massive arborisation within the ‘higher centres’ and the limbic system. Anatomically, glutamate and GABA signalling is characterised by point-to-point communication between narrowly separated (and tethered) pre-synaptic and post-synaptic elements, whereas for monoamine systems, the release sites (boutons) and post-synaptic receptors are not necessarily in close proximity. In contrast to glutamate and GABA, which convey a fast, discrete, short-lived electrical signal, monoamines evoke slower-onset, diffuse, longer-duration biochemical changes in their target neurons. Monoamine systems are not optimised for the rapid dissemination of specific information, but instead for modulating those neurons that are.

Ensemble formation and Gestalts
Pyramidal neurons (the principal output neuron of the hippocampus and cortex) use glutamate as a transmitter to communicate rapidly with neurons in ‘lower centres’ such as the striatum, thalamus, pontine nuclei and the cord although most communication is with other pyramidal neurons. Pyramidal neurons organise themselves into ensembles. This process, in which pyramidal neurons fire in synchrony for brief periods of time is thought to be essential for object perception and for movement, speech and thinking.

Consider a pyramidal neuron ‘sitting’ at resting-membrane-potential (-70mV). It receives tens of thousands of excitatory (glutamate) inputs on its dendritic spines, (dynamic structures that are moulded by experience over a lifetime). A single excitatory input (by itself) has little overall impact on the pyramidal neuron. But when numerous EPSP’s from a multitude of inputs arrive ‘synchronously’, the depolarisation may be sufficient for the pyramidal neuron to fire an action potential (AP). In short, the pyramidal neuron is recruited (by the ensemble) into joining the ensemble.

It can be grasped that for AP firing to occur in a pyramidal neuron, there has to be a convergence of excitatory information from numerous sources. Excitatory inputs come from various thalamic nuclei and from stellate cells (in primary sensory cortices), although the overwhelming majority come from other pyramidal neurons. Regardless of the source, timing is key. In order to generate enough depolarisation to trigger an AP, inputs must arrive (and summate) within the same narrow time window (of the order of milliseconds).

Precise Timing and cortical dynamics
The output of a pyramidal neuron (AP spiking) is finely controlled. Precise timing is so fundamental for cortical processing that various auxiliary neurons appear to be tasked with a pacemaker role. These neurons utilise GABA as a transmitter. Classical neuroscience conceptualised GABA containing neurons as nothing more than inhibitory interneurons – this is no longer tenable. There are various populations of GABA containing neuron, which have been classified according to their morphology, their location in the cortex, which proteins they use to sequester calcium, and their electrophysiological properties. Some are even excitatory. For simplicity, we shall restrict ourselves to a simple classification based upon where the GABA neuron contacts the pyramidal neuron (Figure 2).

glutamate and gaba neurons

Figure 2. A pyramidal neuron receives inhibitory GABA-ergic input to its dendrites. GABA pacemakers synapse on the soma and axon initial segment.

 

Contacts formed with the dendrites of pyramidal neurons function as inhibitory interneurons in the classical sense (i.e. they oppose excitatory drive), whereas GABA neurons targeting the soma or the proximal axon (of the pyramidal neuron) function as pacemakers. We can consider how these GABA pacemaker neurons are optimised for their task. Firstly they have very fast dynamics, swifter for example than the pyramidal neurons that they make contact with. Secondly, they provide a very strong and reliable signal to the pyramidal neuron by engulfing the soma or the proximal axon with numerous terminals. A strong, brief, recurrent signal to the soma and proximal axon creates a series of time windows, which determine precisely when the pyramidal neuron fires. Thirdly, individual pacemaker neurons make contact with numerous local pyramidal neurons. And finally, groups of pacemaker neurons are connected by electrical synapses (gap junctions) so that they can function as an interconnected single entity, a syncytium. For completion, pyramidal neurons make strong, reliable synapses (excitatory) with pacemaker neurons.

It is readily apparent that the interconnectivity of pyramidal neurons and GABA interneurons favours the emergence of oscillations, with successive, precisely timed periods of integration followed by periods of AP discharge. Experiments have shown that the population of neurons in an active ensemble generate the rhythm, whilst the rhythm puts precise constraints upon when an individual neuron can fire.

Systems and levels
For slow, diffuse modulators such as noradrenaline, it makes sense to talk of a system. To recap, noradrenaline [NA] is synthesized by no more than tens of thousands of neurons, confined to discrete nuclei within the brainstem, and is ‘sprayed’ from en-passant boutons over large territories of CNS tissue, in a hormone-like manner. Crucially, the release patterns of noradrenaline [and other neuromodulators] can be clearly mapped onto distinct behavioural states, the most marked differences arising in the sleep-state [noradrenaline – ‘off’] versus the waking-state [noradrenaline – ‘on’]. Since the extracellular concentrations of noradrenaline [and other neuromodulators] can inform directly about higher brain/mind levels, the idea of a noradrenergic system has utility.

Glutamate and GABA are too ubiquitous as fast point-to-point transmitters for the term ‘system’ to be applicable in the same way. Particular patterns of behaviour cannot be mapped onto the release of GABA or glutamate at a specific locus. All we can say is that neurons in an ensemble use glutamate and GABA to communicate with each other. Whereas transient fluctuations in the extracellular concentrations of GABA/glutamate do not reveal anything about behaviour, the dynamics of neuronal ensembles correspond with distinct behavioural states. Again the sleep wake-cycle is illustrative. Oscillatory activity generated by the ensemble can be mapped unambiguously onto the sleep-state and the waking-state.

Learning & Memory
In the 1970s it became clear that excitatory connections onto pyramidal neurons could be made stronger, if they were subjected to particular patterns of input. This was the first experimental support for an idea that can be traced back to Ramon y Cajal – the idea that synapses are modifiable (plastic) and that such plasticity might serve as the physical basis of memory.

There are various forms of plasticity, but the most widely studied is NMDA-dependent long-term potentiation (LTP). In the early 1980’s, researchers based in Bristol showed that NMDA receptor antagonists could block the initiation of LTP [and subsequent behavioural experiments, (most famously, by Richard Morris in Edinburgh) showed that such drugs could inhibit new learning].

NMDA receptor channels are found at the heads of dendritic spines, adjacent to the glutamate terminal. AMPA receptor channels are found in the same locale. When activated, both receptor channels produce an excitatory-post-synaptic-potential (EPSP). In the case of the AMPA receptor, the EPSP is mediated by sodium ions flowing into the spine. For NMDA receptors, the EPSP is mediated by a combination of sodium and calcium ions. [It is the calcium signal that initiates LTP (Figure 3). Early-phase LTP is mediated by phosphorylation of AMPA receptors (increasing their conductance) and by insertion of new AMPA receptors into the post-synaptic membrane].

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

AMPA and NMDA receptor channels differ in one other key property. The NMDA channel is voltage-dependent. At membrane potentials less than -50mV, the NMDA channel remains closed, even if glutamate is bound to the receptor. For the NMDA channel to snap open, the membrane potential must be already depolarised to at least -30mV. So two conditions are necessary for NMDA conductance; binding of glutamate and membrane depolarisation. For this reason, the NMDA receptor is said to be a coincidence detector (or in engineering terms, an AND gate).

Sufficient post-synaptic depolarisation can occur from backward-propagating action potentials (APs) or from temporally or spatially summated excitatory input to a dendritic branch. Research in the last decade has revealed that the timing of pre-synaptic activity (glutamate release) and of post-synaptic activity (post-synaptic-depolarisation) is critical in determining whether synaptic strength will be altered. Pre and post synaptic ‘events’ must occur within approximately 20 milliseconds, otherwise synaptic strength remains unchanged. This form of plasticity, known as Spike-Timing-Dependent-Plasticity (SDTP), is likely to become increasingly relevant as we begin to conceptualise ‘micro-circuit’ abnormalities in major neurodevelopmental disorders. Two final points about SDTP will be made here. Plasticity is bidirectional (potentiation or depression) depending on the order of pre and post-synaptic events. And conventional modulators such as dopamine can impact upon the timing rules and alter the direction of the plasticity, (LTP or LTD).

Some Psychiatry: The K-Hole and beyond
Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, ‘blocks’ the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).

Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counter-intuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of gamma band (~40 Hz oscillations) and some have proposed that ‘kernels’ of ‘abnormal’ gamma underlie the psychotic-like effect.

But the behavioural pharmacology of ketamine is far from straightforward. Rating-scales used in schizophrenia research, are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach [in the sense of ‘bracketing-out’ existing assumptions, whilst focussing on clear descriptions] have identified a much richer and more complex behavioural psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams & Realities 2000).

Close observation reveals the dose-dependent emergence of an oneroid (dream-like) state, and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can ‘cause’ negative symptoms, but reports of euphoria, terror and awe are inconsistent with this categorisation. Motor output (which includes speech of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.

Nevertheless, ketamine is frequently championed as the most convincing drug-model of schizophrenia because it can induce negative symptoms, on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.

Update

Paul Janssen’s genius was in predicting that a drug which blocked the effects of amphetamine in animals, would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterised by agitation, hallucinations and delusions)[link]. That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.

Janssen’s logic would also suggest that a drug which inhibited the effects of ketamine in animals, would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterised by bizarre, inaccessible dream-like states, and psychotic motor phenomena. i.e. cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia. Perhaps this could have been predicted, by closer attention to the phenomenology of ketamine. The question now is whether ‘The Lilly compound‘ has efficacy against non-paranoid schizophrenia?

Natural antidepressants & new brain cells

New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.

 

Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.

curcumin

Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King’s College London provides an excellent summary of work in this area. The full paper can be read here.

 

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