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New Drug Combo Shows Promise for Treatment of Depression and Addiction

Drug Combo Shows Promise for Depression and Addiction
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The combination of naltrexone and ketamine can help treat both symptoms of addiction and depression, a preliminary study by Yale University researchers suggests.

Substance abuse and depression are common in many patients, and efforts to treat both conditions simultaneously have had limited success. One recent study suggested that the antidepressant effects of ketamine might blunted by administration of naltrexone, used to limit cravings of those addicted to opioid drugs and alcohol.

A preliminary study of five patients suffering from both depression and substance abuse disorders suggest that isn’t the case. The study was published Jan. 9 in the journal JAMA Psychiatry.

The results “raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” said senior author John Krystal, Yale’s Robert L. McNeil Jr. Professor of Translational Research; professor of psychiatry, neuroscience, and psychology; and chair of the Department of Psychiatry.

Krystal and lead author Gihyun Yoon, assistant professor of psychiatry, treated the five patients suffering from depression and alcohol use disorder with a long-lasting form of naltrexone and then administered ketamine. Four of the five responded to the first ketamine dose and all five found relief from depression after multiple doses.

The study also challenges the idea that ketamine might produce antidepressant effects by stimulating opiate receptors.

Krystal cautioned that larger studies are needed to confirm beneficial effects of the combination treatment.

Krystal and Yoon have provisional patents on the use of ketamine and naltrexone to treat comorbid depression and substance abuse.

The study was primarily funded by the U.S. Department of Veterans Affairs.

Publication: Gihyun Yoon, et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, 2019; doi:10.1001/jamapsychiatry.2018.3990

At NOVA Health Recovery, we do use Ketamine and other combinations to treat Alcoholism and Opioid and Pain pill addiction using Ketamine Treatment. Dr. Sendi is Board Certified in Addiction Medicine. Call 703-844-0184 Today. Fairfax, Va 22304.



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Intranasal Ketamine for Treatment-Resistant Depression

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NOVA Health Recovery Ketamine Treatment Center

There is an urgent need for better medications that work quickly for treatment of major depression and bipolar disorder. The treatment should also be tolerable and work for depressed patients who have not responded to conventional treatments, ie, who have treatment-resistant depression (TRD).

Ketamine is a medication that is used intravenously for anesthesia, but multiple controlled trials have now demonstrated a rapid antidepressant response to a single intravenous infusion of ketamine. Controlled studies of regular infusions appear promising, but the need for regular IV infusions is not something that is appealing to most patients and often results in non-compliance. And, oral ketamine is extensive broken down by the liver before it can be absorbed by the body, so oral therapy is not a viable option. Therefore, the intranasal route has been investigated.

Intranasal drug delivery offers a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; and the onset of therapeutic action is rapid. Intranasal medications avoid the inconvenience and discomfort of IV therapy. Intranasal medications have been used to treat migraine, acute and chronic pain, Parkinson’s disease, cognitive disorders, autism, schizophrenia, social phobia, and depression.

In a randomized, double-blind, placebo-controlled, crossover trial conducted in 20 patients with major depression, physicians and researchers at the Icahn School of Medicine at Mount Sinai, New York, tested the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. The researchers found that a single intranasal dose of ketamine (50 mg) outperformed placebo; the response rate was 44% versus 6%, respectively. Anxiety ratings also decreased significantly more with ketamine. Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo. Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters like blood pressure.

Intranasal ketamine represents a promising advance in treatment-resistant depression (TRD) therapeutics. Most studies report a duration of response up to 7 days and remission up to 3-5 days after a single dose. “Most adverse events … subsided spontaneously by 60 to 90 minutes post dose,” said Vanina Popova, MD. In addition, “there was no pushback” to the nasal delivery system. “The route of administration was well received, and it was certainly more convenient than intravenous administration,” she said.

Intranasal ketamine is not commercially available, but the clinical use of intranasal ketamine is increasing internationally. Research has concluded that the drug formulation, the delivery device, the technique and individual patient factors play an important role in tolerability and efficacy when using intranasal ketamine for Treatment Resistant Depression.

Intranasal ketamine has been reported in studies to help depressed patients who have not responded to conventional therapy with minimal side effects. Ask our pharmacist for more information about compounded intranasal ketamine. We customize medications to meet each patient’s specific needs.

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References:
Depress Anxiety. 2016 Aug;33(8):698-710. 
Gen Hosp Psychiatry. 2015;37(2):178–184. 
J Clin Psychiatry. 2015 May;76(5):e628-31. 
Biol Psychiatry. 2014 Dec 15;76(12):970-6. 
American Psychiatric Association (APA) 2018. Abstracts P7-065 and P8-054, presented May 8, 2018.
Psychiatry Clin Neurosci. 2018 May 10. 
J Clin Psychiatry. 2017 Jun;78(6):e674-e677. 
CNS Drugs. 2018 May 7. [Epub ahead of print]
J Psychopharmacol. 2018 Apr;32(4):397-407.

Ketamine 25mg – 100 mg Nasal Spray

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial.
METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured.
RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters.
CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression

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What are the uses of ketamine?

Ketamine is a medication that is used to induce loss of consciousness, or anesthesia. It can produce relaxation and relieve pain in humans and animals.

It is a class III scheduled drug and is approved for use in hospitals and other medical settings as an anesthetic.

However, it is also a commonly abused “recreational” drug, due to its hallucinogenic, tranquilizing and dissociative effects.

Controversy has arisen about using ketamine “off-label” to treat depression. Off-label uses of drugs are uses that are not approved by the the United States, (U.S.) Food and Drug Administration (FDA).

Ketamine is safe to use in controled, medical practice, but it has abuse potential. Used outside the approved limits, its adverse mental and physical health effects can be hazardous. Prolonged use can lead to tolerance and psychological addiction.

Fast facts on ketamine:Here are some key points about ketamine. More detail is in the main article.

  • Ketamine is similar in structure to phencyclidine (PCP), and it causes a trance-like state and a sense of disconnection from the environment.
  • It is the most widely used anesthetic in veterinary medicine and is used for some surgical procedures in humans.
  • It is considered a “club drug,” like ecstasy, and it has been abused as a date-rape drug.
  • Ketamine should only be used as prescribed by a doctor.

 

What is ketamine?

ketamine and dissociation
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Ketamine can produce feelings of dissociation when used as a drug of abuse.

Ketamine belongs to a class of drugs known as dissociative anesthetics. It is also known as Ketalar, Ketanest, and Ketaset.

Other drugs in this category include the hallucinogen, phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide, or laughing gas.

These types of drugs can make a person feel detached from sensations and surroundings, as if they are floating outside their body.

 

Therapeutic uses

Ketamine is most often used in veterinary medicine. In humans, it can induce and maintain general anesthesia before, during, and after surgery.

For medical purposes, ketamine is either injected into a muscle or given through an intravenous (IV) line.

It is considered safe as an anesthetic, because it does not reduce blood pressure or lower the breathing rate.

The fact that it does not need an electricity supply, oxygen, or highly trained staff makes it a suitable option in less wealthy countries and in disaster zones.

In human medical practice, it is used in procedures such as:

  • cardiac catheterization
  • skin grafts
  • orthopedic procedures
  • diagnostic procedures on the eye, ear, nose, and throat
  • minor surgical interventions, such as dental extractions

It has been used in a hospital setting to control seizures in patients with status epilepticus (SE), a type of epilepsy that can lead to brain damage and death. However, researchers point out that ketamine is normally used for this purpose after 5 to 6 other options have proven ineffective. Ketamine for the treatment of refractory status epilepticus

It is also an analgesic, and, in lower doses, it can relieve pain.

In 2014, researchers found that a ketamine infusion significantly reduced symptoms of post-traumatic stress disorder (PTSD) in 41 patients who had undergone a range of traumas.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder

Researchers are looking into other possible medical uses of ketamine, particularly in the areas of treatment-resistant depression, suicide prevention, and substance use disorders. However, this use is controversial.

 

Treating depression

Researchers for the American Psychological Association (APA) noted in April 2017 that a number of doctors prescribe ketamine “off-label,” for people with treatment-resistant depression.

However, they caution:

While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

The FDA has not yet approved it for treating depression.

In a study published in BMC Medical Ethics, researchers urge doctors to “minimize the risk to patients” by considering carefully the evidence before prescribing ketamine off-label for patients to treat depression and prevent suicide.

Citing “questionable practice” regarding the prescription of ketamine, they point out that there is not enough evidence to prove that ketamine is safe, and that some studies supporting its use have not been sufficiently rigorous in terms of research ethics.

They call for open debate, more research, and for doctors to try all other options first, before prescribing ketamine.

The National Institutes of Health (NIH) are currently supporting research into whether ketamine may help people with treatment-resistant depression.

 

Effects

Ketamine use can have a wide variety of adverse effects, including:

  • drowsiness
  • changes in perceptions of color or sound
  • hallucinations, confusion, and delirium
  • dissociation from body or identity
  • agitation
  • difficulty thinking or learning
  • nausea
  • dilated pupils and changes in eyesight
  • inability to control eye movements
  • involuntary muscle movements and muscle stiffness
  • slurred speech
  • numbness
  • amnesia
  • slow heart beat
  • behavioral changes
  • increased pressure in the eyes and brain

It can also lead to a loss of appetite, upset stomach, and vomiting.

When used as an anesthetic in humans, doctors combine it with another drug to prevent hallucinations.

Risks

Ketamine is considered relatively safe in medical settings, because it does not affect the protective airway reflexes, and it does not depress the circulatory system, as other anesthetic medications do.

However, some patients have reported disturbing sensations when awakening from ketamine anesthesia.

Ketamine can cause an increase in blood pressure and intracranial pressure, or pressure in the brain.

People with the following conditions cannot receive ketamine for medical purposes:

  • brain swelling
  • glaucoma
  • brain lesion or tumor

It is used with caution in those with:

  • coronary artery disease
  • increased blood pressure
  • thyroid disease
  • chronic alcohol addiction
  • acute alcohol intoxication
  • aneurysm
  • chest pain
  • mental illness

These effects may be stronger in people aged over 65 years.

Some people may have an allergy to the ingredients. Patients with any type of allergy should tell their doctor before using any medication.

Anyone who is using this drug for therapeutic purposes on a regular basis should have regular blood pressure checks.

As a drug of abuse

Ketamine is most often used in the dance club setting as a party drug. It produces an abrupt high that lasts for about an hour. Users report euphoria, along with feelings of floating and other “out of body” sensations. Hallucinations, similar to those experienced with LSD, are common.

In 2014, 1.4 percent of 12th graders reported using ketamine for recreational purposes. This was down from 2002, when 2.6 percent reported using it.

Street names include:

  • Cat Valium
  • KitKat
  • Special K
  • Vitamin K
  • The horse tranquilizer
  • Ket
  • Purple
  • Super K
  • Jet

It is taken orally as a pill, snorted, smoked with tobacco or marijuana, or mixed into drinks. Most often, it is cooked into a white powder for snorting. Taken orally, it can cause severe nausea and vomiting.

Regardless of how it is ingested, its effects begin within a few minutes and last for less than an hour.

Higher doses can produce more intense effects known as being in the “K-hole,” where users become unable to move or communicate and feel very far away from their body.

Some users seek out this type of transcendental experience, while others find it terrifying and consider it an adverse effect.

Adverse effects

Unwanted effects include:

  • addiction
  • psychosis
  • amnesia
  • impaired motor function
  • high blood pressure
  • respiratory problems
  • seizures

As the user can become oblivious to their environment, ketamine abuse puts the person at risk of accidental injury to themselves and vulnerable to assault by others.

Problems with co-ordination, judgment, and the physical senses can continue for up to 24 hours. If an individual is using ketamine in a recreational setting, a sober friend should remain with them to ensure their safety.

Long-term effects include bladder and kidney problems, stomach pain, and memory loss.

If addiction and dependence develop, there is also a risk of depression.

Frequent, illegal use of ketamine can lead to serious mental disorders and major physical harm to the bladder, known as ketamine-induced ulcerative cystitis.

Ketamine and alcohol

Ketamine toxicity alone is unlikely to lead to death, according to the WHO. However, combining it with other substances, such as alcohol, can increase the sedative effects, possibly leading to a fatal overdose.

In the U.S., 1,550 emergency department (ED) visits were due to illegal ketamine use, and 71.5 percent of these also involved alcohol.

Overdose

The risk of overdose is high, because, for a recreational user, there is only a slight difference in dosage between obtaining the drug’s desired effects and an overdose.

Addiction

Ketamine is a Class III controlled substance. Prolonged use can cause dependence, tolerance, and withdrawal symptoms. Quitting can lead to depression, anxiety, insomnia, and flashbacks.

Chronic users have been known to “binge” their ketamine use in an attempt to experience again the dissociative, euphoric effects of their early first use.

The complications of long-term use can be fatal.

A final word

Ketamine is an anesthetic drug, used in human and veterinary medicine. It is important to distinguish the valid medical uses from the non-medical, recreational use of the drug.

When properly administered by a trained medical professional, ketamine is a safe and valuable medication.

Used in recreational settings, however, ketamine abuse can produce unpredictable physical and mental health results. In the long term, it can lead to psychological damage and, in some cases, death.

Any drug use should be prescribed by a doctor who knows the patient’s full medical history.

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Trippy depression treatment? Hopes and hype for ketamine
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Lauren Pestikas sits as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. Pestikas struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year. (AP Photo/Teresa Crawford)

CHICAGO (AP) — It was launched decades ago as an anesthetic for animals and people, became a potent battlefield pain reliever in Vietnam and morphed into the trippy club drug Special K.

Now the chameleon drug ketamine is finding new life as an unapproved treatment for depression and suicidal behavior. Clinics have opened around the United States promising instant relief with their “unique” doses of ketamine in IVs, sprays or pills. And desperate patients are shelling out thousands of dollars for treatment often not covered by health insurance, with scant evidence on long-term benefits and risks.

Chicago preschool teacher Lauren Pestikas long struggled with depression and anxiety and made several suicide attempts before trying ketamine earlier this year.

The price tag so far is about $3,000, but “it’s worth every dime and penny,” said the 36-year-old.

Pestikas said she feels much better for a few weeks after each treatment, but the effects wear off and she scrambles to find a way to pay for another one.

For now, ketamine has not received approval from the U.S. Food and Drug Administration for treating depression, though doctors can use it for that purpose.

Some studies show ketamine can provide relief within hours for tough-to-treat depression and suicidal behavior and clinics promising unproven benefits have popped up nationwide. But more research is needed to know long-term benefits and risks. (Oct. 31)

Ketamine has been around since the 1960s and is widely used as an anesthesia drug during surgery because it doesn’t suppress breathing. Compared to opioids such as morphine, ketamine isn’t as addictive and doesn’t cause breathing problems. And some studies have shown that ketamine can ease symptoms within hours for the toughest cases.

Its potential effects on depression were discovered in animal experiments in the late 1980s and early 1990s showing that glutamate, a brain chemical messenger, might play a role in depression, and that drugs including ketamine that target the glutamate pathway might work as antidepressants.

Conventional antidepressants like Prozac target serotonin, a different chemical messenger, and typically take weeks to months to kick in — a lag that can cause severely depressed patients to sink deeper into despair.

703-844-0184 | Ketamine Treatment Center | Fairfax , VA 22306 | Loudon, Va
A vial of ketamine, which is normally stored in a locked cabinet, on display in Chicago on July 25, 2018. AP Photo/Teresa Crawford)

Ketamine’s potential for almost immediate if temporary relief is what makes it so exciting, said Dr. Jennifer Vande Voort, a Mayo Clinic psychiatrist who has used ketamine to treat depression patients since February.

“We don’t have a lot of things that provide that kind of effect. What I worry about is that it gets so hyped up,” she said.

The strongest studies suggest it’s most useful and generally safe in providing short-term help for patients who have not benefited from antidepressants. That amounts to about one-third of the roughly 300 million people with depression worldwide.

“It truly has revolutionized the field,” changing scientists’ views on how depression affects the brain and showing that rapid relief is possible, said Yale University psychiatrist Dr. Gerard Sanacora, who has done research for or consulted with companies seeking to develop ketamine-based drugs.

But to become standard depression treatment, he said, much more needs to be known.

Last year, Sanacora co-authored an American Psychiatric Association task force review of ketamine treatment for mood disorders that noted the benefits but said “major gaps” remain in knowledge about long-term effectiveness and safety. Most studies have been small, done in research settings and not in the real world.

When delivered through an IV, ketamine can cause a rapid increase in heart rate and blood pressure that could be dangerous for some patients. Ketamine also can cause hallucinations that some patients find scary.

“There are some very real concerns,” Sanacora said. “We do know this drug can be abused, so we have to be very careful about how this is developed.”

Dr. Rahul Khare, an emergency medicine specialist in Chicago, first learned about ketamine’s other potential benefits a decade ago from a depressed and anxious patient he was preparing to sedate to fix a repeat dislocated shoulder.

“He said, ‘Doc, give me what I got last time. For about three weeks after I got it I felt so much better,’” Khare recalled.

Khare became intrigued and earlier this year began offering ketamine for severe depression at an outpatient clinic he opened a few years ago. He also joined the American Society for Ketamine Physicians, formed a year ago representing about 140 U.S. doctors, nurses, psychologists and others using ketamine for depression or other nonapproved uses.

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Dr. Rahul Khare poses for a portrait at his outpatient Chicago clinic on July 25, 2018. (AP Photo/Teresa Crawford)

There are about 150 U.S. ketamine clinics, compared with about 20 three years ago, said society co-founder Dr. Megan Oxley.

Khare said the burgeoning field “is like a new frontier” where doctors gather at meetings and compare notes. He has treated about 50 patients with depression including Pestikas. They’re typically desperate for relief after failing to respond to other antidepressants. Some have lost jobs and relationships because of severe depression, and most find that ketamine allows them to function, Khare said.

Typical treatment at his clinic involves six 45-minute sessions over about two weeks, costing $550 each. Some insurers will pay about half of that, covering Khare’s office visit cost. Patients can receive “booster” treatments. They must sign a four-page consent form that says benefits may not be long-lasting, lists potential side effects, and in bold letters states that the treatment is not government-approved.

At a recent session, Pestikas’s seventh, she leaned back on a reclining white examining-room chair as a nurse hooked her up to a heart and blood pressure monitor. She grimaced as a needle was slipped into the top of her left palm. Khare reached up with a syringe to inject a small dose of ketamine into an IV bag hanging above the chair, then dimmed the lights, pulled the window curtains and asked if she had questions and was feeling OK.

“No questions, just grateful,” Pestikas replied, smiling.

Pestikas listened to music on her iPhone and watched psychedelic videos. She said it was like “a controlled acid trip” with pleasant hallucinations. The trip ends soon after the IV is removed, but Pestikas said she feels calm and relaxed the rest of the day, and that the mood boost can last weeks.

Studies suggest that a single IV dose of ketamine far smaller than used for sedation or partying can help many patients gain relief within about four hours and lasting nearly a week or so.

Exactly how ketamine works is unclear, but one idea is that by elevating glutamate levels, ketamine helps nerve cells re-establish connections that were disabled by depression, said ketamine expert Dr. Carlos Zarate, chief of experimental therapies at the National Institute of Mental Health.

A small Stanford University study published in August suggested that ketamine may help relieve depression by activating the brain’s opioid receptors.

Janssen Pharmaceuticals and Allergan are among drug companies developing ketamine-like drugs for depression. Janssen leads the effort with its nasal spray esketamine. The company filed a new drug application in September.

Meanwhile, dozens of studies are underway seeking to answer some of the unknowns about ketamine including whether repeat IV treatments work better for depression and if there’s a way to zero in on which patients are most likely to benefit.

Until there are answers, Zarate of the mental health institute said ketamine should be a last-resort treatment for depression after other methods have failed.

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Ketamine and Depression

ketamine

ketamine

Introduction

What comes to mind when you think of Ketamine? A drug of abuse? A horse tranquiliser? An anaesthetic agent? In reality it is all three. It usually has short-term hallucinogenic effects or causes a dissociative feeling (e.g. detachment from reality, sedation, or  inability to move). However, with frequent use over time it can cause permanent problems such as ‘ketamine bladder’, resulting in pain and difficulty passing urine.

What we already know

 

Ketamine’s effects are mainly mediated via NMDA (N-methyl-D-aspartate) receptor antagonism, although it is also an agonist at some opioid receptors and interacts with various other receptors, including noradrenaline, serotonin and muscarinic cholinergic receptors.

It is a class B illicit substance and was, in fact, upgraded from class C in June 2014 following a review of its harmful effects. Ketamine (either intramuscularly or intravenously) is licensed for use as an anaesthetic agent in children, young people and adults, but over the last few years interest has been growing in the role of Ketamine as an antidepressant agent. It is not currently licensed for this purpose.

Areas of uncertainty

A study published in 2013 suggested that a single injected dose of Ketamine was associated with a rapid-onset antidepressant effect in patients with treatment-resistant depression (Murrough et al). The biggest challenge in terms of research with ketamine is that it remains tricky to compare against a placebo, given the fairly obvious side effects of taking a hallucinogenic drug, but this study compared Ketamine with Midazolam and this is probably the best comparator so far.

The following year, an open label study was published, which found similar antidepressant effects but a whole host of adverse effects were identified (Diamond et al), including anxiety and panic symptoms, increased suicidal ideation, vomiting, headaches and the anticipated feelings of detachment, confusion and dissociative symptoms.

There was a paucity of good quality information until, in 2015, a systematic review and meta-analysis of 21 studies  showed that single ketamine infusions produced a significant anti-depressant effect for up to seven days. Beyond this time, there was no evidence to suggest a prolonged effect.

What’s in the pipeline

There is some evidence to suggest that Ketamine may also work for Post-Traumatic Stress Disorder and Obsessive Compulsive Disorder. Another proposed use for Ketamine (currently being researched at the University of Manchester) is as an adjunct for Electroconvulsive Therapy (ECT), potentially minimizing the cognitive impairments experienced post-ECT.

Ketamine remains one of the most promising new treatments for depression, both unipolar and bipolar, but it is not without its problems. Requiring specialist referral and a stay in hospital overnight for a single dose clearly has financial and logistical implications far beyond those of antidepressant tablets with a stronger evidence base behind them. We also need more information about safety and adverse effects, before it can be introduced to a wider market.

References

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum. Psychopharmacol Clin Exp. [Abstract]

Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR and McShane R. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic (PDF). J Psychopharmacol, 0269881114527361, first published on April 3, 2014. [PDF]

Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M. et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression; a two-site randomized controlled trial. Am J Psychiatry, 170, 1134-1142. [Abstract]

The antidepressant effects of ketamine are confirmed by a new systematic review and meta-analysis

shutterstock_18453376In recent times, few drugs have caused more excitement among clinical researchers than ketamine. It’s well known for its role in anaesthesia and veterinary surgery (“horse tranquilizer”), as well as its illicit use, but progress has been ongoing for about 15 years to repurpose it as an antidepressant.

As a consequence, many new studies are published every month that evaluate to what extent ketamine lives up to its promise as a new antidepressant drug (Aan Het Rot, Zarate, Charney, & Mathew, 2012). To make sense of the flood of new information, naturally intrigued mental elves clearly need researchers to provide timely updates of the current state of knowledge. To this end, Coyle and Laws (2015) have recently published an extensive systematic review and the first meta-analysis that summarises the latest, methodologically sound research.

The key questions of interest to these researchers were:

  • Does ketamine have an immediate effect in reducing depressive symptoms?
  • Are the antidepressant effects of ketamine sustained over time?
  • Are repeat infusions more effective in reducing depressive symptoms?
  • Do primary diagnosis and experimental design moderate the impact of ketamine on depressive symptoms?
  • Do men and women experience differences in the antidepressant effect of ketamine?

This review looked at how well the effects of ketamine are maintained over

This review looked at how well the effects of ketamine are maintained over 4 hours, 24 hours, 7 days and 12-14 days.

Methods

The authors followed PRISMA guidelines and scanned all relevant medical databases for studies assessing the antidepressant potential of ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). To evaluate possible methodological factors and design variables, the authors also specifically assessed whether studies were: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre-post/placebo-controlled design and patients’ sex.

Effect sizes were calculated either relative to placebo or relative to baseline, in case no control group was provided. To correct for bias in small studies, a Hedge’s g procedure with random effects was used. Statistical heterogeneity, publication bias and moderator variables were assessed to have an idea of other variables that might influence the reported antidepressant potential of ketamine. Statistical heterogeneity among studies was assessed using I² values, with values above 50% generally representing substantial heterogeneity.

Results

In total, 21 studies enrolling 437 patients receiving ketamine were identified that satisfied inclusion criteria:

  • 17 were single infusion studies and the majority reported data collected at 4h (11) and 24h (13) after ketamine treatment
  • 6 studies had follow-up for 7 days
  • 4 studies had follow-up for 12-14 days

In general, there are grounds to assume publication bias for single infusion studies at 4h and 24h.

Of the 21 included studies, 2 were judged to be at a high risk of bias, 13 medium risk and 6 low risk of bias.

  • In general, ketamine had a large statistical effect on depressive symptoms that was comparable across all time points
  • Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days
  • For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days
  • The overall pooled effect sizes for single and repeated ketamine infusions found no difference at any time point, suggesting that the antidepressant effects of ketamine are maintained for at least 12-14 days

table3

Moderator analyses suggest that responsiveness to ketamine may vary according to diagnosis. Specifically, while ketamine produced moderate to large effects in both MDD and BD patients, the effect of a single infusion was significantly larger in MDD than BD after 24h. On the other hand, after 7 days, this pattern reversed and ketamine showed higher efficacy in BD patients. However, the small number of studies makes it tricky to draw any conclusions.

In addition, single-infusion pre-post comparisons did not differ in effect size estimation from placebo-controlled designs except for at 12-14 days, where only one study was available. In a similar vein, there were no effect size differences between single infusion studies with open-label and blinded infusions.

Of note, the meta-analysis found the percentage of males in the group was positively associated with ketamine’s antidepressant effects after 7 days, although this finding warrants replication with more data points.

There's huge room for improvement in the primary research, but this analysis shows ketamine in a promising light as an antidepressant.

There’s plenty of room for improvement in the primary research, but this meta-analysis shows ketamine in a promising light as an antidepressant.

Conclusions

The authors conclude:

Single ketamine infusions elicit a significant anti-depressant effect from 4h to 7days; the small number of studies at 12-14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis – 24 h for MDD and 7 days for BD. The majority of published studies have used pre-post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.

Limitations

This meta-analysis suffers from several limitations that are inherent in the available studies:

  • For one, there were only four studies that assessed the effect of repeated ketamine infusions, which is a shame given that maintenance of antidepressant effects is one of the key drawbacks of rapidly acting interventions
  • In addition, the authors note that their results suggest publication bias, which may be taken to indicate that several negative findings have not been published and thus could not be included in this meta-analysis
  • Also, more information about adverse effects would have been useful, especially to evaluate whether ketamine can be safely applied in a broader clinical context

Summary

This is the first meta-analysis to evaluate ketamine’s antidepressant effects. For single infusion specifically, ketamine exerts large antidepressant effects in MDD as well as BD patients that seem to last at least 7 days, while too few studies are available beyond this time point.

It’s noteworthy that the effect sizes did not differ between time points, which indicates that the effect of a single infusion remains relatively stable in the short-term. While repeated infusions were shown to provide higher effects than single infusions at least for the first week, more studies are needed to corroborate the supremacy of repeated treatment.

Before ketamine can become a clinically viable treatment option, however, this review makes it clear that more methodologically refined studies (especially RCTs with adequate placebo controls) need to be conducted. With this in mind, researchers should take these findings as an incitement to action!

High quality

High quality placebo controlled trials are needed to drive forward progress in this field.

Links

Primary paper

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysisHum. Psychopharmacol Clin Exp, doi: 10.1002/hup.2475. [PubMed abstract]

Other references

Aan Het Rot, M., Zarate, C. a, Charney, D. S., & Mathew, S. J. (2012). Ketamine for depression: where do we go from here? Biological Psychiatry72(7), 537–47. doi:10.1016/j.biopsych.2012.05.003

VA Using Ketamine for PTSD and Depression | IV Ketamine for Depression | 703-844-0184 | Alexandria, Va | 22306 | Ketamine therapy | IV Ketamine center | Ketamine doctor | Springfield, Va | Fairfax, Va 22314 22304

VA Using Ketamine for PTSD and Depression | IV Ketamine for Depression | 703-844-0184

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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

email@novahealthrecovery.com  << Email for questions to the doctor

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Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

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The VA Recognizes Ketamine As An Emergency Treatment For PTSD And Depression Patients At High Suicide Risk

CLEARWATER, Fla., Sept. 27, 2018 /PRNewswire/ — Long used as an safe and effective sedative for surgery, Ketamine has found new life as a treatment for severe depression, PTSD and suicidal ideation. Praised by some mental health experts, the drug so far has achieved very good results in clinical trials. The military now recognizes its’ potential, and last fall Brooke Army Medical Center in San Antonio became part of study on its effects. BAMC will treat active-duty troops with Ketamine, while a VA hospital near Yale will treat veterans. Another study is currently underway at a Veterans Affairs medical center in Cleveland, Ohio. The VA is trying to stem the tide of rising suicide rates among veterans, which average 22 per day – that’s one suicide every 65 minutes.

A staff psychiatrist at the Louis Stokes Cleveland VA Medical Center in Ohio, Dr. Punit Vaidya stated “30% of individuals with major depression don’t respond to traditional medications, so people can become desperate for things that work, because they can have a huge impact on their quality of life, and their overall functioning. The effects of the ketamine infusion can often be seen within a day, if not hours,” Vaidya explained. “If you look at their depression ratings and suicidal ratings given right before treatment and even four hours later you can see a significant reduction and I think that’s really quite remarkable,” Vaidya said.

Dr. Ashraf Hanna, a board certified physician and director of pain management at the Florida Spine Institute in Clearwater, Florida discusses PTSD and Treatment-Resistant Depression: “There are many forms of depression that can be treated by a psychiatrist with various modalities, anti-depressants and psychotherapy. IV Ketamine therapy is only reserved for those patients that have Treatment-Resistant Depression that have failed conventional therapy. IV Ketamine infusion therapyhas offered a new hope to patients that had no hope.”

When asked what prompted his use of IV Ketamine for PTSD and Depression and if any universities were involved in its development, Dr. Hanna went on to say: “There have been multiple universities involved in the research such as Harvard, Yale and Stanford that have proven the success rate of IV Ketamine for treatment-resistant depression. Since I was already successfully using IV Ketamine for CRPS/RSD,FibromyalgiaNeuropathy, and Post-Treatment Lyme Disease Syndrome, with over 10,000 infusions to date, I wanted to expand the treatment for PTSD, Depression, bipolar and Obsessive Compulsive Disorders. Since I am not a psychiatrist, I do not treat depression, but I work with qualified psychiatrists, and if he or she feels the patient has failed other treatment modalities, I then administer IV Ketamine for treatment-resistant depression.”

Dr. Bal Nandra and Ketamine patient Jason LaHood on how Ketamine is redefining the way patients are treated for depression

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Links for Ketamine Articles

  1. NYMag.com – What It’s Like to Have Your Severe Depression Treated With a Hallucinogenic Drug
    http://nymag.com/scienceofus/2016/03/what-its-like-to-treat-severe-depression-with-a-hallucinogenic-drug.html
  2. Huffington Post – How Ketamine May Help Treat Severe Depression
    http://www.huffingtonpost.com.au/2017/04/05/how-ketamine-may-help-treat-severe-depression_a_22027886/
  3. Murrough, Iosifescu, Chang et al. Antidepressant Efficacy in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial  Am J Psychiatry. 2013 Oct 1, 170(10): 1134-1142
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/
  4. Murrough, Perez, Pillemer, et al.. Rapid and Longer0Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression Biol Psychiatry 2013 Aug 15; 74(4): 250-256
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725185/
  5. Murrough, Burdick, Levitch et al. Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial Neuropsychopharmacology 2015 Apr; 40(5): 1084-1090
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367458/
  6. Feder, Parides, et al. Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder A Randomized Clinical Trial Jama Psychiatry 2014 June;71(6): 681-8
    http://jamanetwork.com/journals/jamapsychiatry/fullarticle/1860851
  7. Schwartz, Murrough, Iosifescu Ketamine for treatment-resistant depression: recent developments and clinical applications Evid Based Ment Health 2016 May; 19(2):35-8
    http://ebmh.bmj.com/content/ebmental/19/2/35.full.pdf
  8. Rodriguez, Kegeles, et al Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept Neuropsychopharmacology 2013 Nov; 38(12): 2475-2483
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799067/pdf/npp2013150a.pdf
  9. Singh, Fedgchin, Daly et al. A Double-Blind, Randomized, Pacebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry 2016 August; 173(8): 816-826
    http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2016.16010037
  10. Taylor,  Landeros-Weisenberger, Coughlin et al. Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial  Neuropsychopharmacology 2017 August;
    https://www.ncbi.nlm.nih.gov/pubmed/28849779

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WHAT CAN I EXPECT AT AN INFUSION VISIT?

We will ask you to fast for 8 hours before your infusion. Once you have checked in, you will complete a questionnaire to assess your current status. The IV will be started in your hand or your arm using a small catheter. This may feel like a sting from a small bug bite. The Ketamine will be administered through your IV over a period of 40 minutes. We will take your vital signs before, during, and after the infusion. After resting for an additional 15-20 minutes after the infusion, you will be discharged home with your driver.

  1. What is Ketamine? 
    Ketamine is an anesthetic drug that has been available since the 1960’s. In high doses, it can cause a ‘dissociative anesthesia” which induces hypnosis like states as well as unconsciousness. Around 2000, scientists started looking at Ketamine IV infusions carefully when its clinical usefulness was expanded to include a role in the management of mood disorders as well as chronic pain.
  2. Why can I not drive the day of the infusion?
    Ketamine is a potent anesthetic. As with any anesthetic, we advise our patients to NOT operate any heavy machinery for the remainder of the day due to potential residual effects.
  3. What are the side effects?
    Less than 2% of people will experience side effects. Some of the common side effects are: drowsiness, nausea, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Most of these symptoms dissipate after the first hour of receiving the infusion.
  4. Are there certain conditions that are contra-indications for Ketamine treatment?
    Yes. If you have a history of cardiovascular disease, uncontrolled hypertension, history of psychosis, history of failed Ketamine infusion treatment, history of substance abuse or dependence within the year (patients will undergo a screening process) you will not qualify for Ketamine infusion treatments.
  5. How will I know if I need a booster infusion and how frequently will I require them?
    The duration of antidepressant efficacy after the initial treatment is different for everyone. The studies show that the variance can be 15 days to indefinitely. This is quite a range and unfortunately, there are no predictors for the duration.
  6. Is there a guarantee that this will work for me?
    Unfortunately, we cannot give guarantees.  Studies have shown that 70% of people will obtain efficacy.  After the first 2 infusions, we will be able to ascertain whether the infusions will work for you. We will not advise you to continue your treatment after the first 2 infusions if we do not see a certain amount of improvement.
  7. Isn’t Ketamine addictive? 
    Ketamine has the potential to be addictive. Studies have shown that at these doses and frequency, Ketamine is not addictive.
  8. Do I have to continue my current treatments for depression? 
    Yes. We advise that you alert your current health care provider that you are undergoing these treatments and that you maintain your current regimen.  It can be dangerous to stop taking your medications without the care of a physician. Our patients have a brighter outlook and a positive drive after their treatment that has allowed them to have higher success rates with psychotherapy. We will be happy to work with your current health care provider to provide the optimal outcome.

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VA Using Ketamine for PTSD and Depression

KETAMINE for depression and Magnesium| 703-844-0184 | Ketamine IV doctors | FAIRFAX, VA 22304 | KETAMINE FOR DEPRESSION | KETAMINE FOR ANXIETY | KETAMINE CLINIC |

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog

Ketamine Virginia = Ketamine IV Drip Doctors

The IV Medical Center - IV Vitamin Drips for wellness and recovery


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Magnesium is essential for our health. It is a key cofactor for our energy regulation, and in plants it is the center of the chlorphyll molecule. Low magnesium in people is associated with depression. Among the treatments we provide at the IV Medical Center is Ketamine infusions. In the process of our treatments, we assess patients for toher medical conditions that may lead to refractory depression and low magnesium is one of them.

 

 

Ketamine, an anesthetic and street drug known as “Special K” has garnered a lot of attention for it’s ability, in some, to relieve the symptoms of very severe depression in a matter of minutes. A recent study has demonstrated how it might work, but before you go signing up for a clinical trial (and there are currently many going on in the US), it’s important to understand the downsides to the drug. One major problem is that the effects wear off, usually within 10 days, leaving you just as depressed as before. It can cause urinary incontinence, bladder problems, addiction, and, with chronic use, it can worsen mental health problems, causing more depression, anxiety, and panic attacks.

Ketamine seems to have a remarkable, short term ability to heal the synapses injured by chronic stress. However, anything that acts that quickly and successfully usually has a long-term cost. All powerfully addictive drugs work on our own natural receptors and neurons. Cocaine, for example, causes immediate racing euphoria by inhibiting the natural neurotransmitter dopamine from being recycled, leaving bunches of dopamine in the synaptic cleft. In the very short term, you feel great. In the long term, you tax the system by driving the neurotransmitter system far out of balance in an aggressive way.

Nicotine has a similar effect on the alpha-7 nicotinic receptor. It activates it in a pleasing way, but unfortunately desensitizes the receptor so much that only nicotine will keep it firing. A nutrient found in foods such as egg yolks called choline activates the same receptor, but without desensitizing it.  Long term, regular ingestion of choline keeps the receptor functional and happy, helping with certain brain tasks. Long term, regular use of nicotine activates the receptor but forces you to take more nicotine to keep the receptor working, leaving you foggy-headed and less sharp if you go without cigarettes.

So is there a less dramatic, “natural” version of ketamine, something we can safely ingest every day, but might be a little depleted in our modern diets? Nothing taken in physiologic amounts would reverse a depression in half an hour like ketamine, but could another chemical we find in food and mineral water help with resilience to stress, synaptic repair, and make us more resistant to depression and anxiety symptoms? Sure—that chemical is the mineral magnesium. Magnesium, like ketamine, acts as an antagonist to the NMDA receptor, which means it is a counter to glutamate, the major excitatory neurotransmitter in the brain. The exact mechanisms are complex, but both ketamine and magnesium seem to help glutamate do its job, activating the receptor, without damaging the receptor with too much activation, which, chronically, leads to excitotoxicity, synaptic degradation, inflammation, and even cell death.

One of the exciting things about ketamine is that it works in some people with severe treatment resistant depression who have failed the traditional therapies. Treatment-resistant individuals tend to have lower intracellular magnesium levels than normal (1). Ketamine and magnesium may also work synergistically, complementing each other. Ketamine leads to an increase of intracellular magnesium, and ketamine will reverse the normally seen magnesium decreases after brain trauma (2). There is some evidence also that more standard antidepressant medications, such as imipramine, work in part by reversing the magnesium-depleting effects of chronic stress, suggesting that adding magnesium supplementation to standard antidepressant regimens might help the medications work better (at least in rodents) (3).

It’s great to see an interesting compound like ketamine be taken seriously and thoroughly studied for its action in serious, resistant depression. Ultimately its usefulness may be limited to hospitalized patients who can be closely monitored for the side effects, and who also may benefit the most from the quick mechanism of action, while the longer term risks may be outweighed by the short term benefit in such a critical, serious situation. I would love to see a much safer compound, the mineral magnesium, be studied as an adjunct treatment.

In the mean time, magnesium supplementation is generally safe for most folks with normal kidney function. Many folks eating a normal Western Diethave a low intake of the mineral (4). Those with bowel obstructions, very slow heart rate, or dangerously low blood pressure should not take it. Magnesium can interfere with the absorption of certain medicines (digoxin, nitrofurantoin, bisphosphanates, and some anti malaria drugs). Here are some excellent food sources of magnesium (though remember that both nuts and grains have phytates, which bind minerals, so the magnesium you absorb may not be quite as much as the magnesium you ingest.) Magnesium is also available in many mineral waters.

 

Lets digress over Choline. Choline has impact on decreasing schizophrenia in the children of mother’s who supplement the right amount during pregnancy:

Recently in the American Journal of Psychiatrya new paper was published tying nutrient supplementation in pregnant women to positive changes in the brains of their offspring. One of the nutrients that may be less predominant in our modern diets than in traditional diets is the phospholipid known as choline. Phospholipids are exceedingly important for brain development and neuron signaling.

In the current study, 100 pregnant women were randomized to receiving a daily choline supplement (equivalent to the amount of choline found in 3 large eggs) or placebo. After the babies were born, the choline babies continued to get a supplement equal to 100mg of choline daily (the institutes of medicine recommend total daily choline in infants to be 125mg daily), and at measurements of “cerebral inhibition” were taken at about one month and three months of age. Cerebral inhibition is a term used to describe the ability of the brain to tune out a stimulus that happens over and over. For example, if you are trying to work, and someone is running a jackhammer on the street outside, if you have intact cerebral inhibition, your brain will respond less and less to the sound of the jackhammer as it continues. Presumably this change would allow you to focus on more important things, such as the work at hand.

Source: http://www.flickr.com/photos/anniemole/5268772776/sizes/m/

In some brain disorders, such as schizophrenia, cerebral inhibition is impaired. For someone with schizophrenia, the signal from the jackhammer would be just as strong the second and the third and the seventh and the eighth times. You can imagine how you might be affected if you couldn’t tune anything out, if your brain was constantly taking in more stimulation and unable to sort through what was necessarily important or not. It could be this lack of cerebral inhibition (which begins with brain development in utero and early infancy) is one of the central causes of developing schizophrenia later on. The brain, so overwhelmed with stimuli, stops making sense of it, leading to psychosis and eventually the degeneration of neurons.

Cerebral inhibition is typically measured by a test called the p50 evoked potential. Electrodes are placed on the scalp, and then the subject is exposed to a sensory stimulus, in this case, paired sounds. With intact cerebral inhibition, the second time the brain processes the sound, the wave amplitude of the auditory evoked potential 50 milliseconds after the sound will be much less than the first time. (Go to this image from the American Journal of Psychiatry to see what the waveforms look like in healthy controls and subjects with schizophrenia.

P50 evoked potential abnormalities can be seen in infants, and genes that are associated with a higher risk of schizophrenia are also associated with these abnormal evoked potential tests. Choline is known to cross the placenta and help with the brain development of certain receptors that normalize cerebral inhibition. In the study of pregnant women receiving choline supplements, 76% of the infants whose mothers got choline had normal p50 evoked potential tests at age one month. Only 43% of the infants of the mothers who received placebo had tests consistent with intact cerebral inhibition. In addition, a gene known as CHRNA7 correlated with diminished cerebral inhibition in the placebo group of infants, but not in the choline group. That means that it is possible (though there is way too little data to know) the choline supplementation could reduce the risk of schizophrenia in these infants. The ScienceDaily write up of the study can be found here.

Schizophrenia risk is higher in the offspring of malnourished mothers. There is also a known gene that reduces choline levels that is associated with a higher risk of schizophrenia. Choline is also sequestered in the mother’s liver during trauma, anxiety, or depression, depriving the fetus. Measures of developmental delay and other developmental problems are also associated with later risk of schizophrenia.

Nicotine activates but also profoundly desensitizes the same receptor that choline seems to protect and activate (the alpha-7 nicotinic receptor). 90% of people with schizophrenia smoke, and smoking normalizes p50 evoked potential tests is schizophrenia. Smoking in mothers has been associated with poorer infant cerebral inhibition and later childhood behavioral problems, whereas choline has only been shown to be beneficial for brain development. One difference between the two compounds (among many!) is that choline does not desensitize the alpha-7 nicotinic receptor at all, leaving it active so it can play its presumed role in helping with intact cerebral inhibition.

While choline supplementation is the interest of researchers, I’m more interested in having pregnant women eat their meat and egg yolks, the best sources of choline in the diet. Egg yolks are jam packed with great nutrients for the brain, not only choline, but also B vitamins and other fatty acids important for nerve growth. Bananas also have more choline than you would expect for a fruit. Choline levels in the diet have fallen recently with folks restricting their egg and organ meat consumption. These traditional foods have some important nutrients that we don’t want to skimp on in our diets.

 

Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

Choline, an essential nutrient similar to the B vitamin and found in foods such as liver, muscle meats, fish, nuts and eggs, when given as a dietary supplement in the last two trimesters of pregnancy and in early infancy, is showing a lower rate of physiological schizophrenic risk factors in infants 33 days old. The study breaks new ground both in its potentially therapeutic findings and in its strategy to target markers of schizophrenia long before the illness itself actually appears. Choline is also being studied for potential benefits in liver disease, including chronic hepatitis and cirrhosis, depression, memory loss, Alzheimer’s disease and dementia, and certain types of seizures.

Robert Freedman, MD, professor and chairman of the Department of Psychiatry, University of Colorado School of Medicine and one of the study’s authors and Editor of The American Journal of Psychiatry, points out, “Genes associated with schizophrenia are common, so prevention has to be applied to the entire population, and it has to be safe. Basic research indicates that choline supplementation during pregnancy facilitates cognitive functioning in offspring. Our finding that it ameliorates some of the pathophysiology associated with risk for schizophrenia now requires longer-term follow-up to assess whether it decreases risk for the later development of illness as well.”

Normally, the brain responds fully to an initial clicking sound but inhibits its response to a second click that follows immediately. In schizophrenia patients, deficient inhibition is common and is related to poor sensory filtering and familial transmission of schizophrenia risk. Since schizophrenia does not usually appear until adolescence, this trait — measurable in infancy — was chosen to represent the illness.

Half the healthy pregnant women in this study took 3,600 milligrams of phosphatidylcholine each morning and 2,700 milligrams each evening; the other half took placebo. After delivery, their infants received 100 milligrams of phosphatidylcholine per day or placebo. Eighty-six percent of infants exposed to pre- and postnatal choline supplementation, compared to 43% of unexposed infants, inhibited the response to repeated sounds, as measured with EEG sensors placed on the baby’s head during sleep.

 


Journal Reference:

  1. Randal G. Ross et al. Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia RiskAmerican Journal of Psychiatry, 2013; DOI: 10.1176/appi.ajp.2012.12070940
  2. Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia Risk

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Ketamine, magnesium and major depression–from pharmacology to pathophysiology and back.

Ketamine, magnesium and major depression e From pharmacology to pathophysiology and back

Abstract

The glutamatergic mechanism of antidepressant treatments is now in the center of research to overcome the limitations of monoamine-based approaches. There are several unresolved issues. For the action of the model compound, ketamine, NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be involved in a mechanism, which leads to synaptic sprouting and strengthened synaptic connections. The link to the pathophysiology of depression is not clear. An overlooked connection is the role of magnesium, which acts as physiological NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine with that of high doses of magnesium in animal models, finally leading to synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as measured by an increase in slow wave sleep in humans. 3. Pathophysiological mechanisms, which have been identified as risk factors for depression, lead to a reduction of (intracellular) magnesium. These are neuroendocrine changes (increased cortisol and aldosterone) and diabetes mellitus as well as Mg(2+) deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg(2+) levels in comparison to health controls. 5. Experimental Mg(2+) depletion leads to depression- and anxiety like behavior in animal models. 6. Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts to increase brain Mg(2+) levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg(2+) levels tend to be therapy refractory. Accordingly, administration of Mg(2+) either alone or in combination with standard antidepressants acts synergistically on depression like behavior in animal models.

CONCLUSION:

On the basis of the potential pathophysiological role of Mg(2+)-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg(2+) levels. Furthermore, screening for compounds to increase neuronal Mg(2+) concentration could be a promising instrument to identify new classes of antidepressants. Overall, any discussion of the glutamatergic system in affective disorders should consider the role of Mg(2+)

 

So back to the magnesium and Ketamine issue: As above, Low magnesium seems to be present in individuals who are depressed and have sleeping disorders. The magnesium is not the type measured by standard blood tests as most magnesium is intracellular. Magnesium may play an important role by antagomizing the NMDA receptors as does Ketamine. Our deficient diets in Magnesium may be increasing our rates of depression!

Magnesium as the original Chill Pill

Source: http://www.flickr.com/photos/derekskey/3219004793/

Magnesium is a vital nutrient that is often deficient in modern diets. Our ancient ancestors would have had a ready supply from organ meats, seafood, mineral water, and even swimming in the ocean, but modern soils can be depleted of minerals and magnesium is removed from water during routine municipal treatment. The current RDA for adults is between 320 and 420mg daily, and the average US intake is around 250mg daily.

Does it matter if we are a little bit deficient? Well, magnesium plays an important role in biochemical reactions all over your body.  It is involved in a lot of cell transport activities, in addition to helping cells make energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, you can experience muscle cramps, arrythmias, and even sudden death. Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.

That doesn’t mean that magnesium is unimportant in the brain. Au contraire!In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant (but referenced) speculation into the PubMed database. Fortunately, I don’t need to publish in Medical Hypothesis, as I can engage in such speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas – and it has a lot of interesting information about our essential mineral magnesium.

Magnesium is an old home remedy for all that ails you, including “anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness.” In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability – all reversible with magnesium repletion.

Stress is the bad guy here, in addition to our woeful magnesium deficient diets. As is the case with other minerals such as zinc, stress causes us to waste our magnesium like crazy – I’ll explain a bit more about why we do that in a minute.

Let’s look at Eby’s case studies from his paper:

A 59 y/o “hypomanic-depressive male”, with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and bad diet (“fast food”). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his “feeling of wellness.” A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.

A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, “constant noise,” and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.

A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was “healthy, full weight, and quiet.”

A 40 year-old “irritable, anxious, extremely talkative, moderately depressed” smoking, alchohol-drinkingcocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcoholdisappeared. His “ravenous appetite was supressed, and … beneficial weight loss ensued.”

Eby has the same question about the history of depression that I do – why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (though phytic acid in grains will bind minerals such as magnesium, so the amount you eat in whole grains will generally be more than the amount you absorb). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency.

Beyond Eby’s interesting set of case studies are a number of other studies linking the effects of this mineral to mental health and the stress response system. When you start to untangle the effects of magnesium in the nervous system, you touch upon nearly every single biological mechanism for depression. The epidemiological studies (1) and some controlled trials (2)(3) seem to confirm that most of us are at least moderately deficient in magnesium. The animal models are promising (4). If you have healthy kidneys, magnesium supplementation is safe and generally well-tolerated (up to a point)(5), and many of the formulations are quite inexpensive. Yet there is a woeful lack of well-designed, decent-sized randomized controlled trials for using magnesium supplementation as a treatment or even adjunctive treatment for various psychiatric disorders.

Let’s look at the mechanisms first. Magnesium hangs out in the synapse between two neurons along with calcium and glutamate. If you recall, calcium and glutamate are excitatory, and in excess, toxic. They activate the NMDA receptor. Magnesium can sit on the NMDA receptor without activating it, like a guard at the gate. Therefore, if we are deficient in magnesium, there’s no guard. Calcium and glutamate can activate the receptor like there is no tomorrow. In the long term, this damages the neurons, eventually leading to cell death. In the brain, that is not an easy situation to reverse or remedy.

And then there is the stress-diathesis model of depression, which is the generally accepted theory that chronic stress leads to excess cortisol, which eventually damages the hippocampus of the brain, leading to impaired negative feedback and thus ongoing stress and depression and neurotoxicity badness. Murck tells us that magnesium seems to act on many levels in the hormonal axis and regulation of the stress response. Magnesium can suppress the ability of the hippocampus to stimulate the ultimate release of stress hormone, it can reduce the release of ACTH (the hormone that tells your adrenal glands to get in gear and pump out that cortisol and adrenaline), and it can reduce the responsiveness of the adrenal glands to ACTH. In addition, magnesium can act at the blood brain barrier to prevent the entrance of stress hormones into the brain. All these reasons are why I call magnesium “the original chill pill.”

If the above links aren’t enough to pique your interest, depression is associated with systemic inflammation and a cell-mediated immune response. Turns out, so is magnesium deficiency. In addition, animal models show that sufficient magnesium seems to protect the brain from depression and anxiety after traumatic brain injury (6), and that the antidepressants desipramine and St. John’s Wort (hypericum perforatum) seem to protect the mice from the toxic effects of magnesium deficiency and its relationship to anxious and depressed behaviors (4).

The overall levels of magnesium in the body are hard to measure. Most of our body’s magnesium is stored in the bones, the rest in the cells, and a very small amount is roaming free in the blood. One would speculate that various mechanisms would allow us to recover some needed magnesium from the intracellular space or the bones if we had plenty on hand, which most of us probably don’t. Serum levels may be nearly useless in telling us about our full-body magnesium availability, and studies of levels and depression, schizophrenia, PMS, and anxiety have been all over the place (7). There is some observational evidence that the Mg to Ca ratio may be a better clue. Secondly, the best sources of magnesium in the normal Western diet are whole grains (though again, phytates in grains will interfere with absorption), beans, leafy green veggies, and nuts. These happen to be some of the same sources as folate, and folate depletion is linked with depression, so it may be a confounding factor in the epidemiological studies.

Finally, magnesium is sequestered and wasted via the urine in times of stress. I’m speculating here, but in a hunter-gatherer immediate stress sort of situation, maybe we needed our neurons to fire on all cylinders and our stress hormones to rock and roll through the body in order for us to survive. Presumably we survived or didn’t, and then the stressor was removed, and our paleolithic diets had plenty of magnesium to replace that which went missing. However, it may not be overall magnesium deficiency causing depression and exaggerated stress response – it may just be all that chronic stress, and magnesium deficiency is a biomarker for chronic stress. But it doesn’t hurt to replete one’s magnesium to face the modern world, and at least the relationships should be studied thoroughly. Depression is hugely expensive and debilitating. If we could alleviate some of that burden with enough mineral water… we should know whether that is a reasonable proposition.

As I mentioned before, there are only a few controlled trials of magnesium supplementation and psychiatric disorders. A couple covered premenstrual dysphoria, cravings, and other symptoms (8)(9). Another small study showed some improvement with magnesium supplementation in chronic fatigue syndrome (10). Two open-label studies showed some benefit in mania (11)(12). There is another paper that postulates that magnesium deficiency could exacerbate the symptoms of schizophrenia. However, there is nothing definitive. Which is, of course, quite troubling. How many billions of dollars have we spent on drug research for depression, bipolar disorder, and schizophrenia, when here is a cheap and plausibly helpful natural remedy that hasn’t been properly studied?

So everyone get out there and take some magnesium already!  Whew.  Well, just a few more things to keep in mind before you jump in.

There are some safety considerations with respect to magnesium supplementation. If you have normal kidney function, you do not have myasthenia gravis, bowel obstruction, or bradycardia, you should be able to supplement without too many worries. In addition, magnesium interferes with the absorption of certain pharmaceuticals, including dixogin, nitrofurantoin, bisphosphanates, and some antimalaria drugs. Magnesium can reduce the efficacy of chloropromazine, oral anticoagnulants, and the quinolone and tetracycline classes of antibiotics.

Magnesium oxide is the cheapest readily available formulation, as well as magnesium citrate, which is more likely to cause diarrhea in excess. (In fact, magnesium is a great remedy for constipation). The oxide is not particularly bioavailable, but the studies I’ve referenced above suggest that you can top yourself off after about a month of daily supplementation. Those with short bowels (typically due to surgery that removes a large section of bowel) may want to supplement instead with magnesium oil. You can also put some Epsom salts in your bath. In addition to diarrhea, magnesium can cause sedation, and symptoms of magnesium toxicity (again, quite unlikely if your kidneys are in good shape) are low blood pressure, confusion, arrythmia, muscle weakness, and fatigue. Magnesium is taken up by the same transporter as calcium and zinc, so they can fight with each other for absorption. Jaminet and Jaminet recommend total daily levels (between food and supplements) of 400-800mg. Most people can safely supplement with 200-350mg daily without any problems (again, don’t proceed without a doctor’s supervision if you have known kidney disease or if you are elderly).

People looking for good (but not all paleo) food sources can go here (also a good link for more information on the other formulations of magnesium – there are many!), here, and here.

 

Following are some foods and the amount of magnesium in them:[23]

 

MAGNESIUM  

Magnesium Webpage as below

 

Summary

Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams of magnesium. Over 60% of all the magnesium in the body is found in the skeleton, about 27% is found in muscle, 6% to 7% is found in other cells, and less than 1% is found outside of cells (1).

Function

Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP)(3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for additional discussions regarding the role of PTH) (3).

Cell migration

Calcium and magnesium levels in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions

Zinc

High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4).

Fiber

Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).

Protein

Dietary protein may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was lower when protein intake was less than 30 grams/day, and higher protein intakes (93 grams/day vs. 43 grams/day) were associated with improved magnesium absorption in adolescents (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium levels are known to result in low blood calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).

Deficiency

Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (1):

  • Gastrointestinal disorders: Prolonged diarrhea, Crohn’s diseasemalabsorption syndromesceliac disease, surgical removal of a portion of the intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion.
  • Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).
  • Chronic alcoholism: Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion, which is frequently encountered in alcoholics.
  • Age: Several studies have found that elderly people have relatively low dietary intakes of magnesium (7, 8). Intestinal magnesium absorption tends to decrease with age and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was decreased serum magnesium levels (hypomagnesemia). Over time, serum calcium levels also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium levels. As the magnesium depletion progressed, PTH secretion diminished to low levels. Along with hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium levels (hypokalemia), retention of sodium, low circulating levels of PTH, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the recommended dietary allowance (RDA) for magnesium, based on the results of recent, tightly controlled balance studies that utilized more accurate methods of measuring magnesium (2Table 1). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimum health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 30 (AI) 30 (AI)
Infants 7-12 months 75 (AI) 75 (AI)
Children 1-3 years 80 80
Children 4-8 years 130 130
Children 9-13 years 240 240
Adolescents 14-18 years 410 360
Adults 19-30 years 400 310
Adults 31 years and older 420 320
Pregnancy 18 years and younger 400
Pregnancy 19-30 years 350
Pregnancy 31 years and older 360
Breast-feeding 18 years and younger 360
Breast-feeding 19-30 years 310
Breast-feeding 31 years and older 320

Disease Prevention

Metabolic syndrome

Low magnesium intakes have been associated with the diagnosis of metabolic syndrome. The concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertensioninsulin resistance, and obesity, increases the risk for type 2 diabetes mellitus and cardiovascular disease. Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 middle-aged women; the lowest prevalence of metabolic syndrome was found in the group of women with the highest quintile of magnesium intakes (median intake, 422 mg/day) (9).

Hypertension (high blood pressure)

Large epidemiological study studies suggest a relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effects of magnesium on blood pressure. A prospective cohort study of more than 30,000 male health professionals found an inverse association between dietary fiber, potassium, and magnesium and the development of hypertension over a four-year period (10). In a similar study of more than 40,000 female registered nurses, dietary fiber and dietary magnesium were each inversely associated with systolic and diastolic blood pressures in those who did not develop hypertension over the four-year study period, but neither dietary fiber nor magnesium was related to the risk of developing hypertension (11). The Atherosclerosis Risk in Communities (ARIC) study examined dietary magnesium intake, magnesium blood levels, and risk of developing hypertension in 7,731 men and women over a six-year period (12). The risk of developing hypertension in both men and women decreased as serummagnesium levels increased, but the trend was statistically significant only in women.

However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium levels might not best reflect magnesium status. A recent prospective study that followed 5,511 men and women for a median period of 7.6 years found that the highest levels of urinary magnesium excretion corresponded to a 25% reduction in risk of hypertension, but plasma magnesium levels were not correlated with risk of hypertension (13). In cohort of 28,349 women followed for 9.3 years, the risk of hypertension was 7% lower for those with the highest magnesium intakes (434 mg/day vs. 256 mg/day) (14). The relationship between magnesium intake and risk of hypertension suggests that magnesium supplementation might play a role in preventing hypertension; however, randomized controlled trials are needed to assess whether supplemental magnesium might help prevent hypertension in high-risk individuals.

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest (268 mg/day) (15). However, inclusion of this study in a meta-analysis of eight cohort studies showed that risk of type 2 diabetes was inversely correlated with magnesium intake (15). A second meta-analysis found that an increase of 100 mg/day in magnesium intake was associated with a 15% decrease in the risk of developing type 2 diabetes (16). The most recent meta-analysis of 13 observational studies, published in the last 15 years and including almost 540,000 individuals and 24,500 new cases of diabetes, found higher magnesium intakes were associated with a lower risk of diabetes (17).

Insulin resistance, which is characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to magnesium deficiency. An inverse association between magnesium intakes and fasting insulin levels was evidenced in a meta-analysis of 11 cohort studies that followed more than 36,000 participants without diabetes (18). It is thought that pancreatic β-cells, which regulate insulin secretion and glucose tolerance, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (19). A randomizeddouble-blindplacebo-controlled trial, which enrolled 97 individuals (without diabetes and with normal blood pressure) with significant hypomagnesemia (serum magnesium level ≤0.70 mmoles/L), showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin levels (20). Increased insulin sensitivity also accompanied the correction of magnesium deficiency in patients diagnosed with insulin resistance but not diabetes (21). Another study found that supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 47 overweight individuals even though they displayed normal values of serum and intracellular magnesium (22). This suggests that magnesium might have additive effects on glucose tolerance and insulin sensitivity that go beyond the normalization of physiologic serum concentrations in deficient individuals.

Cardiovascular disease

A number of studies have found decreased mortality from cardiovascular disease in populations who routinely consume “hard” water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than “soft” water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (23). One large prospective study (almost 14,000 men and women) found a significant trend for increasing serum magnesium levels to be associated with decreased risk of coronary heart disease (CHD) in women but not in men (24). However, the risk of CHD in the lowest quartile of dietary magnesium intake was not significantly higher than the risk in the highest quartile in men or women. This prospective study was included in a meta-analysis of 14 studies that found a 22% lower risk of CHD (but not fatal CHD) per 200 mg/day incremental intake in dietary magnesium (25). In another prospective study, which followed nearly 90,000 female nurses for 28 years, women in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal myocardial infarction) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (26). Higher magnesium intakes were associated with an 8%-11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (27, 28). Additionally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (29). Finally, a meta-analysis of six prospective studies found no association between magnesium intake and cardiovascular mortality risk (30). However, a recent prospective study that followed 3,910 subjects for 10 years found significant correlations between hypomagnesemia and all-cause mortality, including cardiovascular-related mortality (31). Presently, well-controlled intervention trials are required to assess the benefit of magnesium supplementation in the prevention of cardiovascular disease.

Stroke

Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage caused by the rupture of a cerebral aneurysm (32). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (33). Magnesium sulfate is a calcium antagonist and potent vasodilator that has been considered in the prevention of vasospasm after aSAH. Several randomized controlled trials have assessed the effect of intravenous (IV) magnesium sulfate infusions. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (34). The most recent meta-analysis of 13 trials in 2,413 aSAH patients concluded that the infusion of magnesium sulfate had no benefits in terms of neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (35). At present, the data advise against the use of intravenous magnesium in clinical practice for aSAH patients after normalization of their magnesium status.

Complications of heart surgery

Atrial arrhythmia is a condition defined as the occurrence of persistent heart rate abnormalities that often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (36). However, a meta-analysis of five randomized controlled trials concerned with rhythm-control prophylaxis showed that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (37). Presently, the findings support the use of β-blockers and amiodarone, but not magnesium, in patients with contraindications to first-line antiarrhythmics.

Osteoporosis

Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral components of bone may result in bones that are brittle and more susceptible to fracture. Magnesium comprises about 1% of bone mineral and is known to influence both bone matrix and bone mineral metabolism. As the magnesium content of bone mineral decreases, apatite crystals of bone become larger and more brittle. Some studies have found lower magnesium content and larger apatite crystals in bones of women with osteoporosis compared to women without the disease (38). Inadequate serum magnesium levels are known to result in low serum calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). A study of over 900 elderly men and women found that higher dietary magnesium intakes were associated with increased BMD at the hip in both men and women. However, because magnesium and potassium are present in many of the same foods, the effect of dietary magnesium could not be isolated (39). A cross-sectional study in over 2,000 elderly individuals reported that magnesium intake was positively associated with total-body BMD in white men and women but not in black men and women (40). More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water was inversely correlated with risk of hip fracture (41).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for the first six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (42). A study in postmenopausal women who were taking estrogen replacement therapy and also a multivitamin found that supplementation with an additional 500 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving only estrogen replacement therapy (43). Evidence is not yet sufficient to suggest that supplemental magnesium could be recommended in the prevention of osteoporosis unless normalization of serum magnesium levels is required. Moreover, it appears that high magnesium levels could be harmful to skeletal health by interfering with the action of the calciotropic hormones, PTH and calcitriol (44). Presently, the potential for increased magnesium intake to influence calcium and bone metabolism warrants more research with particular attention to its role in the prevention and treatment of osteoporosis.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific diseases is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential risks of high doses of supplemental magnesium, especially in the presence of impaired kidney function, any disease treatment trial using magnesium doses higher than the UL should be conducted under medical supervision.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are pregnancy-specific conditions that may occur anytime after 20 weeks of pregnancy through six weeks following birth. Approximately 7% of pregnant women in the US develop preeclampsia-eclampsia. Preeclampsia (sometimes called toxemia of pregnancy) is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy. Eclampsia occurs with the addition of seizures to the triad of symptoms and is a significant cause of perinatal and maternal death (45). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (46). For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with preeclampsia-eclampsia late in pregnancy or during labor (47, 48). A systematic review of seven randomized trials compared the administration of magnesium sulfate with diazepam (a known anticonvulsant) treatment on perinatal outcomes in 1,396 women with eclampsia. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (46). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of preeclampsia and eclampsia to prevent initial and recurrent seizures (49).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (50). The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (51). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. However, a meta-analysis of five randomized controlled trials, which included a total of 6,145 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy and gross motor dysfunction, without modifying the risk of other neurologic impairments or mortality in early childhood (52). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (53). Nevertheless, additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease

Hypertension (high blood pressure)

While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A recent meta-analysis examined 22 randomizedplacebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either a normal blood pressure (normotensive) or hypertension, both treated or untreated with medications. Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2-3 mm Hg and diastolic blood pressure by 3-4 mm Hg (54); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (55). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals. Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether subjects with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated subjects showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (56), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (57). See the article in the Spring/Summer 2009 Research Newsletter, Dietary and Lifestyle Strategies to Control Blood Pressure.

Myocardial infarction (heart attack)

Results of a meta-analysis of randomizedplacebo-controlled trials indicated that an intravenous (IV) magnesium infusion given early after suspected myocardial infarction(MI) could decrease the risk of death. The most influential study included in the meta-analysis was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (58). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium treated group (59). However, a larger placebo-controlled trial that included more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of the treatment (60). A US survey of the treatment of more than 173,000 patients with acute MI found that only 5% were given IV magnesium in the first 24 hours after MI, and that mortality was higher in patients treated with IV magnesium compared to those not treated with magnesium (61). The most recent systematic review of 26 clinical trials, including 73,363 patients, concluded that IV magnesium likely does not reduce mortality following MI and thus should not be utilized as a treatment (62). Thus, the use of IV magnesium sulfate in the therapy of acute MI remains controversial.

Endothelial dysfunction

Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 63). Research studies have indicated that pharmacologic doses of oral magnesium may improve endothelial function in individuals with cardiovascular disease. A randomizeddouble-blindplacebo-controlled trial in 50 men and women with stable coronary artery disease found that six months of oral magnesium supplementation (730 mg/day) resulted in a 12% improvement in flow-mediated vasodilation compared to placebo (64). In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. Magnesium supplementation also resulted in increased exercise tolerance during an exercise stress test compared to placebo. In another study of 42 patients with coronary artery disease who were already taking low-dose aspirin (an inhibitor of platelet aggregation), three months of oral magnesium supplementation (800 to 1,200 mg/day) resulted in an average 35% reduction in platelet-dependent thrombosis, a measure of the propensity of blood to clot (65). Additionally, a study in 657 women participating in the Nurses’ Health Study reported that dietary magnesium intake was inversely associated with E-selectin, a marker of endothelial dysfunction (66)In vitro studies using human endothelial cells have provided mechanistic insights into the association of low magnesium concentrations, chronic inflammation, and endothelial dysfunction (67). Finally, since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with chronic kidney disease. The atherosclerotic process is often accelerated in these subjects, and patients with chronic kidney disease have higher rates of cardiovascular-related mortality compared to the general population (68). Additional studies are needed to assess whether magnesium may be of benefit in improving endothelial function in individuals at high risk for cardiovascular disease.

Diabetes mellitus

Magnesium depletion is commonly associated with both insulin-dependent (type 1) and non-insulin dependent (type 2) diabetes mellitus. Reduced serum levels of magnesium (hypomagnesemia) have been reported in 13.5% to 47.7% of individuals with type 2 diabetes (69). One cause of the depletion may be increased urinary loss of magnesium, which results from increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes (70). One study reported that dietary magnesium supplements (390 mg/day of elemental magnesium for four weeks) improved glucose tolerance in elderly individuals (71). Another small study in nine patients with type 2 diabetes reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin levels but did not affect fasting glucose levels (72). Yet, the most recent meta-analysis of nine randomizeddouble-blind, controlled trials concluded that oral supplemental magnesium may lower fasting plasma glucose levels in individuals with diabetes (73). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (74). Large-scale, well-controlled studies are needed to determine whether magnesium supplementation has any long-term therapeutic benefit in patients with type 2 diabetes. However, correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in those with diabetes.

Migraine headaches

Individuals who suffer from recurrent migraine headaches have lower intracellular magnesium levels (demonstrated in both red blood cells and white blood cells) than individuals who do not experience migraines (75). Additionally, the incidence of ionized magnesium deficiency has been found to be higher in women with menstrualmigraine compared to women who don’t experience migraines with menstruation (76). Oral magnesium supplementation has been shown to increase intracellular magnesium levels in individuals with migraines, leading to the hypothesis that magnesium supplementation might be helpful in decreasing the frequency and severity of migraine headaches. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (75, 77). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (78). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (79). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19% to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric (stomach) irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (80). The administration of 1 gram of intravenous (IV) magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (81), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (82, 83). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of IV magnesium for migraine in adults (84). However, the effect of magnesium should be examined in larger studies targeting primarily migraine sufferers with hypomagnesemia (85).

Asthma

The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (86). Several clinical trials have examined the effect of intravenous (IV) magnesium infusions on acute asthmatic attacks. One double-blindplacebo-controlled trial in 38 adults with acute asthma, who did not respond to initial treatment in the emergency room, found improved lung function and decreased likelihood of hospitalization when IV magnesium sulfate was infused compared to a placebo (87). However, another placebo-controlled, double-blind study in 48 adults reported that IV infusion of magnesium sulfate did not improve lung function in patients experiencing an acute asthma attack (88). A systematic review of seven randomized controlled trials (five adult and two pediatric) concluded that IV magnesium sulfate is beneficial in patients with severe, acute asthma (89). In addition, a meta-analysis of five randomized placebo-controlled trials, involving 182 children with severe asthma, found that IV infusion of magnesium sulfate was associated with a 71% reduction in the need for hospitalization (90). In the most recent meta-analysis of 16 randomized controlled trials (11 adult and 5 pediatric), IV magnesium sulfate treatment was associated with a significant improvement of respiratory function in both adults and children with acute asthma treated with β2-agonists and systemic steroids (91). At present, available evidence indicates that IV magnesium infusion is an efficacious treatment for severe, acute asthma; however, oral magnesium supplementation is of no known value in the management of chronic asthma (92-94). Nebulized, inhaled magnesium for treating asthma requires further investigation. A meta-analysis of eight randomized controlled trials in asthmatic adults showed that nebulized, inhaled magnesium sulfate had benefits with respect to improved lung function and decreased hospital admissions (91). However, a recent systematic review of 16 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate, along with a β2-agonist, improved pulmonary function in patients with acute asthma (95).

Sources

Food sources

A large US national survey indicated that average magnesium intake is about 350 mg/day for men and about 260 mg/day for women — significantly below the current recommended dietary allowance (RDA). Magnesium intakes were even lower in men and women over 50 years of age (8). Such findings suggest that marginal magnesium deficiency may be relatively common in the US.

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are rich in magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Magnesium
Food Serving Magnesium (mg)
Cereal, all bran ½ cup 112
Cereal, oat bran ½ cup dry 96
Brown rice, medium-grain, cooked 1 cup 86
Fish, mackerel, cooked 3 ounces 82
Spinach, frozen, chopped, cooked ½ cup 78
Almonds 1 ounce (23 almonds) 77
Swiss chard, chopped, cooked ½ cup 75
Lima beans, large, immature seeds, cooked ½ cup 63
Cereal, shredded wheat 2 biscuits 61
Peanuts 1 ounce 48
Molasses, blackstrap 1 tablespoon 48
Hazelnuts 1 ounce (21 hazelnuts) 46
Okra, frozen, cooked ½ cup 37
Milk, 1% fat 8 fluid ounces 34
Banana 1 medium 32

Supplements

Magnesium supplements are available as magnesium oxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acidchelates, including magnesium aspartate. Magnesium hydroxide is used as an ingredient in several antacids (96).

Safety

Toxicity

Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excess magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum levels of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day (Table 3); this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 65
Children 4-8 years 110
Children 9-13 years 350
Adolescents 14-18 years 350
Adults 19 years and older 350
*Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate and etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonate is not inhibited. Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics. Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may result in magnesium depletion (96, 97). Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (98, 99). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400-420 mg/day for men and 310-320 mg/day for women). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement may ensure an intake of at least 100 mg of magnesium/day. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Because magnesium is plentiful in foods, eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual’s magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily. Since older adults are more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).

magnesium-flashcard

 

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Old Club Drug Is Repurposed Into Depression Treatment

A North Texas woman said a popular club drug and animal tranquilizer saved her from a life of depression and suicidal thoughts.

You may have heard of the drug before, as Special K on the street. it was designed as a horse tranquilizer, but Ketamine is gaining popularity as a treatment for depression.

Some doctors believe the controversial drug will become a game-changer in slowing the nation’s suicide epidemic.

Tiffany McCombie, a 40-year-old mother of one, knows what depression feels like in its darkest moments.

“I definitely was feeling what I would consider suicidal, not really wanting to live, not really wanting to die, just numb. That’s not a healthy place for me,” McCombie said.

She said she has lived with depression and Bipolar disorder for 30 years, has tried dozens of medications and supplements to combat it, but nothing, she said, has worked as well as the Ketamine infusions she gets at Rise Wellness Center.

She’s had six of them in ten months.”I had the right attitude and wanted to be healed and believing that it was going to happen for me and my brain. It happened. It cut down the mood stabilizers and antidepressants I had been on for years. I don’t take them at all,” she said.

More studies,like this one, are finding that Ketamine may be more effective and work faster than traditional antidepressants.

A local team of anesthesiologists had used the drug before, as an anaesthetic inside the operating room, but after seeing its potential to treat depression, they opened Rise Wellness Center, which specializes in Ketamine infusions.

“We get people that are so far down and so dark that we need this to get them out, to get them up, to get them moving. No drug does that like Ketamine,” said Dr.  Renaud Rodrigue, a pain management physician at Rise Wellness Center.

Experts say Ketamine can be dangerous, even deadly, if abused or taken in large doses.

Even though it’s not FDA-approved to treat depression, Dr. Rodrigue said, when given in small doses and in a clinical setting, 90 percent of his patients with severe depression reported long-term benefits.

Researchers at the University of Illinois published this study about how Ketamine may trigger a depression-fighting protein in the brain.

“This protein changed the game for us. We know now there’s something that is created just by the drug itself, which is staying in the central nervous system and is exerting this affect way beyond the duration of the drug,” said Dr. Rodrigue.

McCombie said Ketamine saved her life.

Could Ketamine conquer Treatment resistant depression?

A notorious drug that can cause dangerous hallucinations and even death when abused may be the key to treating severely depressed patients when used under proper physician care. UT Southwestern’s Dr. Lisa Monteggia has uncovered how the drug Ketamine works so rapidly and why patients are seeing success when other treatments have failed.

Transcript

{Video opens with music and pictures of UTSW patient Megan Joyce along with her mother and with her husband.}

Megan Joyce: Everything in my life seems great.

Narrator: Megan Joyce’s life may look picture perfect.

Megan: I graduated college. I got married. He’s an amazing person. He is incredibly supportive.

Narrator: But what these happy photos hide is a relentless inner struggle.

Megan: This is not something that I love to admit, but I fight for my life every single day.

Narrator: The 27-year-old has spent more than a decade battling severe depression. It triggers for no obvious reason.

Megan: They have defined my bipolar illness as treatment resistant.

Narrator: She says she tried every medication in the books … as well as checking into inpatient and outpatient treatment centers. Nothing worked. Until doctors at UT Southwestern Medical Center tried something bold. Ketamine infusion therapy.

Megan: I don’t know if I would be here without the Ketamine treatment. I drive from Austin every 10 days, and I come for treatment, and I’m in the hospital for about 5 hours, and then I go home the same day.

Narrator: Several studies show ketamine can quickly stabilize severely depressed patients. But it does come with risks.

Dr. Madhukar Trivedi: There is a risk for addiction so that if people start taking Ketamine on their own on the black market, then that can be very dangerous. There are toxic effects in the brain if you overdose. On the other hand, for patients who do well on this and are getting the right dose under the guidance of a physician, it can be life saving.

Megan: When I have the IV in, it’s for 40 minutes, and then I stay for 2 hours after because it is an anesthetic so they want to make sure you don’t have adverse side effects.

Narrator: Dr. Madukhar Trivedi is closely monitoring Joyce … as well as the work his colleagues are doing at the bench.

Dr. Trivedi: At UT Southwestern, we have the whole breadth of work being done. There are people working like Dr. Monteggia in basic research. Understanding the exact mechanism of how Ketamine changes molecularly and changes the mechanism of action.

Dr. Lisa Monteggia: We got involved with how Ketamine triggers an anti-depressant effect because of the real need. Some of the recent clinical data has really shown that about a third of all patients don’t respond to anti-depressants. So, what do you do for treatment for those individuals?

Narrator: UT Southwestern’s Dr. Lisa Monteggia is a neuroscientist whose lab pinpointed a key protein that helps tigger Ketamine’s rapid antidepressent effects in the brain. Whereas traditional antidepressents can take up to 8 weeks to work, the effects of ketamine are seen within 60 to 90 minutes.

Dr. Monteggia: The idea of trying to understand how you generate a rapid anti-depressant response in patients … it’s really the first time we’ve been able to study it.

Narrator: Her study, published in the prestigious journal Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions.

Dr. Monteggia: How we think Ketamine triggers an anti-depressant effect, this blocking the NMDA receptor, we think may also be causing the side effects associated with Ketamine. One of the things we’re working on is to try and see if we can identify compounds, slight derivatives perhaps, that may have the beneficial effects of Ketamine, in terms of triggering anti-depressant effects, without the side effects.

Narrator: In the meantime, Joyce remains optimistic for her future and the millions of others trying to defeat depression.

Megan: That’s why I really sought out Ketamine is I really wanted to give back and just have a chance at a semi-normal life.

Depression Patients Turning to Local Doctor’s Ketamine Therapy

The deaths of designer Kate Spade on Tuesday and TV Chef Anthony Bourdain Friday morning are bringing new attention to depression and suicide.

A new Center for Disease Control and Prevention report reveals suicide rates have risen 30 percent across much of the country since 1999.

But right here in San Diego, there is hope for a category of patients some doctors call “the untreatable.”

This patient, we’ll call Lisa, is composing a letter to the editor about her 20-year fight to stay alive.

“I know how tall the bridge is. I know how many seconds it takes to land,” Lisa said.

Lisa is an attorney with severe depression. Conventional medicines could not suppress her suicidal thoughts.

“It’s awful,” she said. “The day starts with waking up thinking ‘Can I even get out of bed?’ You just fight it to exhaustion every single day.”

She was referred to Dr. David Feifel who NBC 7 first also spoke to three years ago. Patients travel from as far away as Canada to undergo his Ketamine therapy.

“Sort of a psychedelic experience. It’s also been termed dissociative experience because it is sort of an out-of-body feeling,” Dr. Feifel said of his therapy.

Dr. Feifel says low doses of Ketamine have an almost immediate effect on his patients, unlike conventional anti-depressants that can take weeks to build up a therapeutic level.

While Ketamine doesn’t stay in the body more than a day, its effects can last for months.

“It seems to be able to vaporize people’s sense of wanting to take their life.” Dr. Feifel said.

Lisa has received some 35 treatments over the last four months.

“I walk in here crappy, I’ll leave happy. It is a remarkable, remarkable experience that in 20 years nothing has ever come close” Lisa said.

Her goal is to need fewer treatments and experience longer-lasting effects.

Lisa’s hope for the so-called “untreatable community” of depressed people is they find help.

Ketamine-Associated Brain Changes – A Review of the Neuroimaging Literature

KEY POINTS:

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

Subanesthetic doses of ketamine have rapid (within hours), robust (across a variety of symptoms), and relatively sustained (typically up to one week) antidepressant effects—even in patients with TRD (treatment resistant depression). Clinical studies show that about 50% of patients with TRD have a significant decrease in symptoms within 24 hours of a single intravenous subanesthetic ketamine dose.

Animal models show that ketamine’s antidepressant effects are likely mediated by its antagonism of N-methyl-D-aspartate (NMDA) receptors through increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA)–mediated glutamatergic signaling. This triggers activation of intracellular synaptogenic pathways, most notably in the mechanistic target of rapamycin (mTOR)–signaling pathway, which also has implications in many other psychiatric disorders.

With regard to MDD patients, decreased glutamate has been noted in various prefrontal regions, including the dorsolateral prefrontal cortex (dlPFC), dorsomedial PFC (dmPFC), and anterior cingulate cortex (ACC), when compared to controls.8–10 This shortage of glutamate makes ketamine an ideal treatment for MDD; by creating a surge in glutamate levels in regions of the brain that suffer from a glutamate deficit, ketamine may provide some normalization of glutamate levels in patients with MDD. This “glutamate surge” hypothesis has dominated as the primary theory of ketamine’s antidepressant mechanism.

Ketamine may work through additional receptors, as it is known to have effects on several opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters.17–19 It is also possible that acute dissociative side effects of ketamine may be mediating antidepressant response.

One salient biological metric that may provide insight into ketamine’s mechanism of action is related to dissociation. Dissociative side effects begin from infusion, reach a peak typically within an hour of infusion, and are completely diminished 230 minutes after infusion.20 The same study has shown that increased dissociation and psychotomimetic symptoms immediately following infusion may predict antidepressant response. (Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 2014;159:56–61Do the dissociative side effects of ketamine mediate its antidepressant effects.)

Certain themes have emerged with Ketamine. First are our findings of convergent brain regions implicated in MDD and how ketamine modulates those areas. Specifically, the subgenual ACC has been a region of interest in many previous studies. In relation to emotion and cognition, ketamine appears to reduce brain activation in regions associated with self-monitoring, to increase neural regions associated with emotional blunting, and to increase neural activity in reward processing.

Overall, ketamine’s effects were most notably found in the subgenual ACC, PCC, PFC, and hippocampus. Abnormalities in overlapping regions (specifically, the dorsal and subgenual ACC, amygdala, hippocampus, and ventral striatum) have been implicated, via a growing body of neuroimaging literature, in the pathophysiology of depression.  The subgenual ACC, in particular, has been a frequently studied area of interest concerning ketamine and MDD.

FMRI found significant reductions in subgenual ACC coupling with hippocampus, retrosplenial cortex, and thalamus. Immediate reductions in subgenual ACC blood flow and focal reductions in OFC blood flow strongly predicted dissociation.

NIMH studies using PET 120 minutes postinfusion found that increased metabolism in the subgenual ACC was positively correlated with improvements in depression scores post-ketamine. (Neural correlates of rapid antidepressant response to ketamine in bipolar disorder..)

Analysis of resting-state scans in healthy volunteers further suggests that dissociation may be responsible for ketamine’s antidepressant effects because it may disconnect the “excessive effects of an aversive visceromotor state on cognition and the self”—a hallmark of depression.40(p 163) Related, one study found that ketamine may dampen brain regions involved in rumination (the repetitive focusing of attention on negative feelings and thoughts in response to negative mood) by reducing the functional connectivity between the pregenual ACC and the dorsal PCC, and decreasing connectivity between the left and right executive-control networks.  (. Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35 .Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network.)

Taken together, these studies suggest that ketamine may cause a “disconnect” in several circuits related to affective processing, perhaps by shifting focus of attention away from the internal states of anxiety, depression, and somatization, and more toward the perceptual changes (e.g., hallucinations, visual distortions, derealization) induced by ketamine. Similarly, during an emotion task, ketamine attenuated responses to negative pictures, suggesting that the processing of negative information is specifically altered in response to ketamine. (Scheidegger M, Henning A, Walter M, et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation. Hum Brain Mapp 2016;37:1941–52.Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation)

By taking the focus off “oneself” and placing it on other stimuli, it is possible that ketamine decreases awareness of negative experiences and consequently improves mood.

Perhaps most interesting are ketamine’s effects on brain connectivity as it relates to self-monitoring behaviors. Reduced connectivity between the pregenual ACC and dorsal PCC was associated with increased dissociation during infusion, and reduced activation in the left superior temporalcortex was associated with impaired self-monitoring56,65—which is disruptive to patients with psychotic illness—especially those with chronic symptoms of psychosis. By contrast, the transient dissociation experienced by depressed patients during a ketamine infusion may have the effect of dampening what the hyperactive self-monitoring associated with depressive illness (Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. b)

During ketamine administration, subjects experience emotional blunting, which may be associated with reduced limbic responses to emotional stimuli.54,55 It is possible that by decreasing the activity of deep limbic structures (thought to be involved in the pathophysiology of depression, such as the amygdala), ketamine acutely disables the emotional resources required to perpetuate the symptoms of depression. (Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine and fMRI BOLD signal: distinguishing between effects mediated by change in blood flow versus change in cognitive state. Hum Brain Mapp 2003;18:135–45. Ketamine and fMRI BOLD signal Distinguishing between effects mediated by change in blood flow versus change in cognitive state|||| Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport 2003;14:387–91 Ketamine alters neural processing of facial emotion recognition in healthy men an fMRI study.)

Ketamine may play a role in reactivating reward areas of the brain in patients with MDD. This reactivation may be especially important, as reward areas in MDD have been characterized by decreased subcortical and limbic activity and by an increased cortical response to reward paradigms. (Zhang WN, Chang SH, Guo LY, Zhang KL, Wang J. The neural correlates of reward-related processing in major depressive disorder: a meta-analysis of functional magnetic resonance imaging studies. J Affect Disord 2013;151:531–9.)

In resting-state scans, BOLD activation in the cingulate gyrus, hippocampus, insula, thalamus, and midbrain increased after ketamine.( Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA. Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. J Psychopharmacol 2015;29:1025–8.Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe)

In addition, ketamine increases neural activation in the bilateral MCC, ACC, and insula, as well as the right thalamus.  Activation of these areas is consistent with activation of reward-processing areas, suggesting that ketamine may play a role in activating reward neurocircuitry. (Hoflich A, Hahn A, Kublbock M, et al. Ketamine-dependent neuronal activation in healthy volunteers. Brain Struct Funct 2017;222:1533–42.)

Though no single brain area has been singled out as the locus of depression, ketamine affects different areas of the brain in various ways, which may contribute to overall mood improvements. For example, at baseline, patients with MDD, compared to healthy volunteers, had reduced global connectivity in the PFC and increased connectivity in the posterior cingulate, precuneus, lingual gyrus, and cerebellum; postketamine, responders had increased connectivity in the lateral PFC, caudate, and insula. (Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology 2017;42:1210–9.Ketamine Treatment and Global Brain Connectivity in Major Depression.)

These findings may reflect ketamine’s ability to reclaim frontal control over deeper limbic structures, thus strengthening the cognitive control of emotions and decreasing depressive symptoms. Similarly, TRD patients, compared to healthy volunteers, had reduced insula and caudate responses to positive emotions at baseline, which normalized in the caudate post-ketamine. (Murrough JW, Collins KA, Fields J, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 2015;5:e509 Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.)

Improvements are correlated with increased metabolism in the hippocampus, dorsal ACC, and decreased metabolism in the OFC. (Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol 2015;29:596–607 Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.)

Specifically, based on this review, future studies should likely focus on ketamine’s action in the subgenual ACC, PCC, PFC, and hippocampus. Another promising direction for research builds on the view that depression is the product of underactive prefrontal and limbic mood-regulation networks and overreactive subcortical limbic networks, which are involved in emotional and visceral responses. (Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213:93–118 Brain structural and functional abnormalities in mood disorders.)

Ketamine’s potential use in both research and treatment is promising indeed.

 

Neural correlates of exercise training in individuals with schizophrenia and in healthy individuals A systematic review.

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Ketamine and Ketamine Metabolite Pharmacology Insights into Therapeutic Mechanisms.

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression a perspective review

THE NEUROBIOLOGY OF ketamine and addiction

Psychedelic-Assisted Psychotherapy – A Paradigm Shift in Psychiatric Research and Development

KETAMINE FOR TREATMENT-RESISTANT UNIPOLAR AND BIPOLAR MAJOR DEPRESSION – CRITICAL REVIEW AND IMPLICATIONS FOR CLINICAL PRACTICE.

Ketamine for the treatment of addiction Evidence and potential mechanisms  <<<<<<<<<<<<<<<<<<<<<<<<<<<

REVIEW OF KETAMINE ABUSE AND DIVERSION

Cognitive behavior therapy may sustain antidepressant effects of intravenous ketamine in treatment-resistant depression

The Effect of a Single Dose of Intravenous Ketamine on suicidal ideation – systemic review and meta-analysis

Rapid-Acting Antidepressants Mechanistic Insights and Future Directions.

Ketamine and rapid-acting antidepressants a new era in the battle against depression and suicide.

Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

New Targets for Rapid Antidepressant Action

Role of copper in depression. Relationship with ketamine treatment

Ketamine normalizes brain activity during emotionally valenced attentional processing in depression.

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine.

Recognizing Depression from the Microbiota⁻Gut⁻Brain Axis. b

Psychobiotics and the gut–brain axis in the pursuit of happines

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion

Default Mode Connectivity in Major Depressive diosrder measured up to 10 days after Ketamine administration

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders.

Ketamine for Depression, 2 Diagnostic and Contextual Indications.

Ketamine’s antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder

Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

The role of adipokines in the rapid antidepressant effects of ketamine.

response to ketamine and prediction of treatment outcome

What is the mechanism of Ketamine’s rapid‐onset antidepressant effect A concise overview of the surprisingly large number of possibilities

Medical comorbidity in bipolar disorder The link with metabolic-inflammatory systems.

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

Role of neuro-immunological factors in the pathophysiology of mood disorders.

Anti-inflammatory agents in the treatment of bipolar depression a systematic review and meta-analysis

The role of tryptophan metabolism and food craving in the relation between obesity and bipolar disorder

Immune-based strategies for mood disorders facts and challenges

Metabolic syndrome in psychiatric patients implications

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder.

Case–control association study of 14 variants of CREB1, CREBBP and CREM on MDD and bipolar

Metabolic syndrome in psychiatric patients overview, mechanisms, and implications.

Peripheral inflammation, Physical Activity and Cognition in Bipolar Disorder

The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatruc disorders – chronic fatigue bipolar MS

Bipolar Disorder and Inflammation.

Pharmacologic implications of inflammatory comorbidity in bipolar disorder.

Minding the brain- the role of pharmacotherapy in substance-use disorder treatment

Molecular and Cellular Effects of Traumatic Stress Implications for PTSD

Synaptic Loss and the Pathophysiology of PTSD Implications for Ketamine as a Prototype Novel Therapeutic

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Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

NOVA Health Recovery | 703-844-0184 | Fairfax, Virginia 22304
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Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients << Article link 

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

 

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study  << Article in Clinical Psychiatry

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial Article link for below:

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.”

Ketamine for Rapid Reduction of Suicidal Thoughts in major depression – A midazolam controlled trial PDF article

Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304
Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304

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Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

Abstract
Objective To review the published literature on the efficacy
of ketamine for the treatment of suicidal ideation (SI).
Methods The PubMed and Cochrane databases were
searched up to January 2015 for clinical trials and case
reports describing therapeutic ketamine administration to
patients presenting with SI/suicidality. Searches were also
conducted for relevant background material regarding the
pharmacological function of ketamine.
Results Nine publications (six studies and three case
reports) met the search criteria for assessing SI after
administration of subanesthetic ketamine. There were no
studies examining the effect on suicide attempts or death
by suicide. Each study demonstrated a rapid and clinically
significant reduction in SI, with results similar to previously
described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been
reported in the literature as receiving therapeutic ketamine.
Seven studies delivered a dose of 0.5 mg/kg intravenously
over 40 min, while one study administered a 0.2 mg/kg
intravenous bolus and another study administered a liquid
suspension. The earliest significant results were seen after
40 min, and the longest results were observed up to
10 days postinfusion.
Conclusion Consistent with clinical research on ketamine
as a rapid and effective treatment for depression, ketamine
has shown early preliminary evidence of a reduction in
depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to
further investigate its mechanism of action, long-term
outcomes, and long-term adverse effects (including abuse)
and benefits. In addition, ketamine could potentially be
used as a prototype for further development of rapid-acting
antisuicidal medication with a practical route of administration
and the most favorable risk/benefit ratio.
Key Points
Preliminary data from randomized controlled trials
have demonstrated that ketamine may rapidly and
effectively control treatment-resistant depression,
though the effects are transient.
A small subset of studies has demonstrated similar
results in the effects of ketamine on suicidal ideation.
Ketamine has potential as a rapid treatment for
suicidal ideation and/or a possible model compound
for future drug development.

4 Discussion
With an estimated prevalence of mood disorders ranging
from 3.3 to 21.4 % and the substantially increased risk of
suicide among patients with mood disorders, treatment is
certainly warranted [19]. Current treatment options for
suicidality are limited. They include brain stimulation
therapeutics, such as ECT, and pharmacological intervention
(lithium, clozapine). The efficacy of lithium in treating
suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48
studies [22]. Clozapine has also been shown to reduce
suicide risk in patients with schizophrenia [23, 24]. The
limitations of both lithium and clozapine include a longer
time to efficacy in this psychiatric emergency/urgency,
compared with the early response to ketamine [25]. Ketamine
seems to be gaining substantial evidence as a pharmacological
option for depression with a fast onset of
action, but its long-term effects need further investigation.
In addition, ketamine probably offers a faster onset of
action in terms of SI, but further work is certainly needed
in this area. Given the risk of suicide and even the
increasing rates of suicide in certain subgroups, such as
soldiers and veterans [26, 27], there is an urgent need for
faster therapeutics for SI and TRD. Importantly, suicidality
and suicide pose a high global burden of patient suffering
to families and society. Although several small-to-moderate
sized studies, in addition to several reviews, have been
published that have examined the efficacy of ketamine in
TRD, there are considerably fewer published data
specifically examining ketamine in patients presenting with
SI. Notably, only three studies have directly examined SI
as the primary outcome [11, 16, 17], while the rest
examined SI as the secondary outcome [4, 15, 18], not
including case reports. This review summarizes the current
published literature regarding ketamine as a treatment for
SI. The data so far show promising trends of ketamine
being an effective and rapid treatment with minimal side
effects.
Pharmacologically, ketamine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It has been used for anesthesia
in the USA since the 1970s. At subanesthetic doses,
ketamine has been shown to increase glutamate levels [3].
This mechanism is relevant, as glutamate regulation and
expression are altered in patients with major depressive
disorder (MDD). Studies have also demonstrated an
abnormal glutamate–glutamine–gamma-aminobutyric acid
cycle in patients with suicidality [28]. Furthermore, ketamine
has also been shown to work on nicotinic and opioid
receptors [29]. No other class of antidepressant medication
works to modulate the glutamatergic system, and research
continues into this, with the goal of characterizing the full
mechanism of action of ketamine and perhaps developing
other compounds that would have similar effects. Thus,
even if the approval and marketing of ketamine as a rapidacting
antisuicidal and antidepressant medication is not
realized, it could well be a prototype for development of
other medication(s) that retain the mechanism of action
with more favorable qualities and a lesser adverse effect
profile (such as a longer duration of action or less or no
addictive potential). Although the mechanisms explaining
the antisuicidal effect and the NMDA receptor antagonism
of ketamine are still unclear, some of the initial evidence
points to an anti-inflammatory action via the kynurenic
acid pathway. Strong suggestions as to the causal relationship
between inflammation and depression/suicidality
has come from studies demonstrating that cytokines [30,
31] and interferon-b [32] induce depression and suicidality.
Other recent studies have added to the notion of implicating
brain immune activation in the pathogenesis of suicidality.
For instance, one study showed microglial
activation of postmortem brain tissue in suicide victims
[33]. Another study found increased levels of the cytokine
interleukin-6 in cerebrospinal fluid from patients who had
attempted suicide [34]. Higher levels of inflammatory
markers have been shown in suicidal patients than in nonsuicidal
depressed patients [33, 35]. Inflammation leads to
production of both quinolinic acid (an NMDA agonist) and
kynurenic acid (a NMDA antagonist). An increased
quinolinic acid to kynurenic acid ratio leads to NMDA
receptor stimulation. The correlation between quinolinic
acid and Suicide Intent Scale scores indicates that changes
in glutamatergic neurotransmission could be specifically
linked to suicidality [36].
Small randomized controlled trials have demonstrated
the efficacy of ketamine in rapidly treating patients with
both TRD and/or bipolar depression [4, 8, 9, 11, 16–18].
Some studies have also examined suicide items as a secondary
measure in their depression rating scales [4, 7]. In
total, the studies examining ketamine and TRD have nearly
consistently demonstrated that ketamine provides relief
from depressive and suicidal symptoms, starting at 40 min
and lasting for as long as 5 days. Questions still remain as
to the long-term effects of this treatment, how much should
be administered and how often, any serious adverse effects,
and the mechanism of action.
Pharmacologically, ketamine has poor bioavailability
and is best administered via injection [37]. In their landmark
study, Berman et al. [4] found that a subanesthetic
dose (0.5 mg/kg) rapidly improved depressive symptoms.
Most of the subsequent studies have delivered ketamine as
a constant infusion for 40 min at a rate of 0.5 mg/kg.
Others have examined its efficacy after multiple infusions
and observed similar results [8, 13, 16, 38]. Currently, it is
recommended that ketamine be administered in a hospital
setting [39].

______________________________________

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:

 

Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic
modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after
ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI
response to ketamine.
Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with
DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic
(0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture
modeling to generate SI response classes, and class membership predictors were evaluated using multinomial
logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.
Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders
(44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1.
Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for
Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated
with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to
Remitters rather than Responders.
Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma,
rather than CSF, markers were used.
Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence
from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic
SI were less likely to respond or remit post-ketamine.

1. Introduction
Suicide poses a serious threat to public health. Worldwide, suicide
accounts for approximately 1 million deaths, and 10 million suicide
attempts are reported annually (World Health Organization, 2014). In
the United States, the national suicide rate has increased by approximately
28% over the last 15 years (Curtin et al., 2016). At the same
time, relatively few interventions for suicide risk exist. While treatments
such as clozapine and lithium have demonstrated effects on
suicidal behavior over weeks to months, these effects may be limited to
specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently,
no FDA-approved medications exist to treat suicidal ideation
(SI), leaving those who experience a suicidal crisis with limited options
for a reprieve of symptoms. Consequently, a critical need exists for
rapid-acting treatments that can be used in emergency settings.
A promising off-label agent for this purpose is the rapid-acting antidepressant
ketamine, which past studies have suggested reduces suicidal
thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price
et al., 2009). A recent meta-analysis of 167 patients with a range of
mood disorder diagnoses found that ketamine reduced suicidal
thoughts compared to placebo as rapidly as within a few hours, with
effects lasting as long as seven days (Wilkinson et al., 2017). These
results are reinforced by newer findings of reduced active suicidal
ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era
of personalized medicine, two important issues must be addressed.
First, little is known about the acute course of SI following ketamine.
The speed with which antidepressant response occurs, and how much
improvement can be expected on average, has been documented for
single administrations of ketamine (Mathew et al., 2012; Sanacora
et al., 2017); in the limited available literature, researchers have
emulated previous studies examining antidepressant effect, where a
cutoff of 50% improvement demarcated response (Nierenberg and
DeCecco, 2001). Nevertheless, it remains unknown whether this categorization
accurately reflects the phenomenon of suicidal thoughts.
Empirically-derived approaches to the description of SI trajectory after
ketamine may be useful in operationalizing “response” in future clinical
trials.
Second, identifying demographic, clinical, or biological predictors
of SI response to ketamine would allow researchers and clinicians to
determine who is most likely to exhibit an SI response to ketamine. A
broad literature describes clinical and demographic predictors for suicide
risk (Franklin et al., 2017), and a smaller literature connects suicidal
thoughts and behaviors to plasma markers such as brain-derived
neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015;
Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini
et al., 2013). However, no biomarkers have been shown to predict SI/
behavior response to intervention, a finding reinforced by the National
Action Alliance for Suicide Prevention’s Research Prioritization Task
Force’s Portfolio Analysis (National Action Alliance for Suicide
Prevention: Research Prioritization Task Force, 2015). Notably, predictor
analyses have the potential to reveal insights into personalized
treatments for suicidal individuals, as well as the neurobiology of SI
response. With respect to antidepressant response, for example, this
approach yielded the observation that individuals with a family history
of alcohol dependence may be more likely to exhibit an antidepressant
response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip
et al., 2014).
The goals of this study were to elucidate trajectories of SI response
and identify predictors of that response, with the ultimate goal of
adding to the growing literature surrounding ketamine’s specific effects
on SI. In particular, we sought to determine whether the heterogeneous
patterns of change in SI after ketamine administration were better explained
by a model with two or more latent groups of trajectories rather
than a single average trajectory, using secondary analyses from previously
published clinical trials. These classes were then used to evaluate
potential clinical, demographic, and plasma biomarker predictors
of SI response to ketamine in order to generate hypotheses.. Discussion
This analysis used a data-driven approach to characterize SI response
to ketamine. The data were best explained by three trajectory
classes: one with severe average baseline SI and little to no response to
ketamine (Non-Responders), one with moderate average baseline levels
of SI and significant response to ketamine (Responders), and a third
with moderate average baseline levels of SI and complete remission of
SI by two days post-ketamine (Remitters). These findings suggest a
diversity of post-ketamine changes in SI that may not be captured under
traditional methods of categorizing response to treatment.
Furthermore, we found evidence that SI response and antidepressant
response could be distinguished from each other; one subset of participants
experienced improvement in SI that was partially explained by
improvements in Depressed Mood, while the other group’s improvements
in SI occurred independently of antidepressant response. With
regard to predictors of SI response trajectory, preliminary results suggest
the individuals least likely to experience improvement in SI postketamine
were those with the most severe SI and a history of self-injury.
Few plasma markers emerged as predictors of SI response in this study,
highlighting the limitations of connecting SI ratings of response with
biological markers.
The growth mixture modeling approach used here underscored the
heterogeneity of SI response to ketamine, which would not have been
captured by simply calculating the average trajectory. The class assignment
from this approach also differed from the definition of response
(50% reduction in symptoms) traditionally used in the antidepressant
literature, which often focuses on a specific timepoint rather
than the entire symptom trajectory. In comparing classification using a
50% response at Day 1 and Day 3 with the latent trajectory classes, we
found representation of almost every SI class across each responder
group, highlighting the potential limitations of the 50% response approach.
Further study is needed to determine which of these approaches
will prove more fruitful. Complete remission of SI has previously been
used as an outcome measure in clinical trials and in a meta-analysis of
ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018;
Wilkinson et al., 2017), as well as in a study examining the relationship
between SI response to ketamine and changes in nocturnal wakefulness
(Vande Voort et al., 2017). One strength of the present study is that this
data-driven approach provides classifications that directly reflect the
phenomena under study as they are, as opposed to what they should be.
Especially when used in larger samples than the current study, this
approach is particularly promising in its ability to provide a more
nuanced understanding of the nature of SI response to ketamine.
Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable
by baseline Depressed Mood scores; patients with the most
severe SI did not differ meaningfully in Depressed Mood scores from
those with the mildest SI. Second, while previous analyses of these data
documented that BMI and family history of alcohol dependence predicted
antidepressant response (Niciu et al., 2014), SI response was not
associated with these variables in the current analysis. Third, the antidepressant
response profiles of the SI classes suggest that SI response
and antidepressant response are not wholly redundant. This aligns with
previous clinical trials and meta-analytic reviews of the literature suggesting
that SI response to ketamine occurs partially independently of
antidepressant response (Grunebaum et al., 2018; Wilkinson et al.,
2017). Nevertheless, this independence did not hold true across both SI
response groups. Specifically, antidepressant and SI response were
clearly linked in Remitters, with depression accounting for half of the
changes in SI; however, in Responders, improvements in SI occurred
independently from improvements in Depressed Mood. These discrepancies
could be related to ketamine’s complex neurobiological
mechanisms or to the potentially low levels of clinical severity observed
in the Remitters.
Interestingly, the current analyses found no baseline demographic
variables that reliably distinguished Responders from Remitters. Some
phenotypic characteristics were uniquely associated with belonging to
the Non-Responder group, suggesting that a long-standing history of
self-injury or SI may indicate resistance to rapid changes in SI.
Relatedly, a recent, randomized clinical trial of repeat-dose ketamine
compared to placebo found that ketamine had no effect on SI in a
sample of patients selected for their longstanding, chronic history of SI
(Ionescu, 2017). These results highlight the importance of patient selection,
particularly for suicide risk. It should be stressed, however, that
SI does not necessarily translate to suicidal attempts or deaths; to our
knowledge, no study has yet linked ketamine with reduced risk of
suicidal behavior. Indeed, in the present study the SI Non-Responders
experienced limited antidepressant effects in response to ketamine, but
may nevertheless have improved on other, unmeasured symptoms that
could provide important benefit and relief. As the ketamine literature
develops, it will be important to identify which clinical symptom profiles
are most likely to have a robust anti-SI and anti-suicidal behavior
response to ketamine and which ones may benefit from other interventions.
While we evaluated a range of potential plasma markers previously
linked to suicidal ideation and behavior, in the present analysis only IL5
was associated with the SI Responder subgroup. Ketamine is known to
have anti-inflammatory effects (Zunszain et al., 2013), but the relationship
between antidepressant response and change in cytokine
levels remains unclear (Park et al., 2017). Cytokines have been linked
to suicidal behavior in the past; a recent meta-analysis found that lower
levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated
with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large
number of comparisons and lack of precedent in the literature, this
result may have been spurious and should be interpreted with caution.
A number of other results may reflect meaningful relationships, but the
high degree of variability—and the associated wide confidence intervals—suggests
that larger sample sizes are needed to better elucidate
the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13,
p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly,
plasma BDNF levels were not associated with responder class.
Previous studies of bipolar, but not MDD, samples found that plasma
BDNF levels were associated with SI response after ketamine
(Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed
diagnostic composition of this study may explain differences from
previous work. Studies exploring the relationship between BDNF and
antidepressant response to ketamine have also yielded mixed findings
(Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven
approaches have considered both biological and behavioral variables in
characterizing depression (Drysdale et al., 2017); a similar approach
might prove useful for predicting SI response.
The present study is associated with several strengths as well as
limitations. Strengths include the relatively large sample size of participants
who received ketamine, the use of composite SI scores from
previous exploratory factor analyses as opposed to individual items,
and the combination of clinical and biological markers as potential
predictors of class membership. Limitations include patient selection
methods, as these patients were part of an antidepressant trial and were
not selected for active suicidal thoughts, as well as the exploratory
nature of the analysis. As stated above, suicidal thoughts do not necessarily
equate to suicidal behavior, and class membership would thus
not necessarily correspond with an overall reduction in suicide risk.
Another limitation is that results were collapsed across several clinical
trials with slight variations in study design, and findings were thus only
extended to Day 3 rather than a week after ketamine administration. As
a result, only a subset of the sample could be used for predictive analyses.
In addition, plasma—rather than CSF—markers were used, and
the latter might better indicate underlying biology due to proximity to
the brain, though certain markers such as plasma BDNF may be related
to platelet storage, rather than the brain (Chacón-Fernández et al.,
2016). Comparison of results to trajectories of suicide-specific measures,
such as the Scale for Suicide Ideation (Beck et al., 1979), may also
give further insight into specific SI content. Finally, many clinical
predictors were collected upon hospital admission; future analyses
could use formal assessments, such as the Childhood Traumatic Questionnaire
(Bernstein et al., 1994), assessment of personality disorders,
or diagnoses such as post-traumatic stress disorder (PTSD) as potential
indicators of response.
Despite these limitations, the study demonstrates the utility of a
data-driven approach for characterizing the heterogeneity of SI response
to a rapid-acting intervention. This allows for a more finegrained
analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at
50% reduction in symptoms. This study identified several findings of
note. These included distinguishing at least three patterns of SI response
to ketamine and finding that subjects who exhibited more severe SI at
baseline were not likely to experience an SI response to ketamine.

 

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Ketamine offers a rapid solution for many when their other treatments for depression have failed. Most patients studied for Ketamine treatment have failed standard therapies. Sanjay Gupta discusses this below in the link:

 

KETAMINE as a rapid antidepressant – CNN article Sanjay Gupta

Suicide in the United States