More About Ketamine

For decades, scientists have searched for a new type of antidepressant, one that works differently from the 20-plus drugs already on the market. Finding a new option is crucial, since a third of people don’t respond to available depression treatments.

They haven’t had much luck — except for the discovery that IV infusions of ketamine hydrochloride, an FDA-approved anesthetic, can cause rapid antidepressant effects in many people with stubborn depression.

Gerard Sanacora, a professor of psychiatry at Yale University, has treated hundreds of severely depressed patients with low doses of ketamine, an anesthetic and popular club drug that isn't approved for depression.

This sort of "off-label" prescribing is legal. But Sanacora says other doctors sometimes ask him, "How can you be offering this to patients based on the limited amount of information that's out there and not knowing the potential long-term risk?" Sanacora has a simple answer. "If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they've tried the standard treatments, how do you not offer this treatment?" he says.

When depression takes hold of Helen it feels like she is drowning in a pool of water, unable to swim up to the world above. The 36-year-old former nurse has had mental health problems most of her life. No drugs, hospital stays or therapies have been able to help.

Then one day, during yet another spell in hospital, her consultant told her about a psychiatrist treating patients with ketamine. The psychiatrist in question visited her to discuss using the drug. He warned there were no guarantees, but it had helped some patients.

Antidepressants are among the most commonly prescribed drugs throughout the western world. In fact, they are prescribed more than any other drug for Americans aged 18 to 44, and they are now taken four to five times more frequently than in the early 90s. In the UK, antidepressant use has doubled over the past decade. Either more people are depressed, more people are talking about their depression, or doctors now think they have got a pill that will help.

What are these drugs? Unlike the antidepressants of 30 years ago, they are considered “clean” and well-tailored. They target a certain neurochemical and leave the rest of the brain alone. (Old-school antidepressants were notorious for their scattershot effect.)

Approximately one-third of patients with major depressive disorder (MDD) do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. There is a clear unmet need for rapidly acting and more efficacious treatments. We will review recent developments in the study of ketamine, an old anaesthetic agent which has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD, focusing on clinically important aspects such as dose, route of administration and duration of effect. Additional evidence suggests ketamine may be efficacious in patients with bipolar depression, post-traumatic stress disorder and acute suicidal ideation. We then discuss the safety of ketamine, in which most neuropsychiatric, neurocognitive and cardiovascular disturbances are short lasting; however, the long-term effects of ketamine are still unclear. We finally conclude with important information about ketamine for primary and secondary physicians as evidence continues to emerge for its potential use in clinical settings, underscoring the need for further investigation of its effects.

Post-traumatic stress disorder (PTSD) is highly prevalent in the United States military forces, with rates as high as 31% and 20% for Vietnam War and Operation Iraqi Freedom (OIF) veterans, respectively. An estimated 50% of patients diagnosed with PTSD also present with chronic pain.

In armed forces involved in OIF and Operation Enduring Freedom, fractures and extremity wounds represented 54% of all wounds, and 47% of these patients went on to develop chronic pain.3 Distal extremity trauma and fractures constitute the 2 most common precipitating events for Complex Regional Pain Syndrome II (CRPS).

More than three million Americans suffer with Generalized Anxiety Disorder (GAD). GAD is characterized by excessive worry about routine life events, without any particular reason for this worry. People with GAD feel irritable and edgy and have an unrealistic view of their problems as overwhelming. Their anxiety can interfere with the ability to concentrate and the ability to sleep.

It has been established that blocking the neurotransmitter glutamate can alleviate the symptoms of Generalized Anxiety Disorder, so it is not surprising that ketamine (which is a potent glutamate blocker) can treat it.

The popular club drug ketamine — or 'Special K' — is also a fast-acting antidepressant, but how it works has eluded scientists. Now a team reports in Nature1 that the mood-lifting effect may not be caused by the drug itself, but by one of the products formed when the body breaks the drug down into smaller molecules.

If the findings, from a study in mice, hold true in humans, they could suggest a way to provide quick relief for people with depression — without patients having to experience ketamine’s ‘high’. Such a drug would be welcome news to the many people with major depressive disorder who do not find relief in currently available antidepressants. Ketamine also eases depression in a matter of hours, whereas other drugs take weeks to reach their full effect.

The notorious club drug is shocking scientists with its ability to treat severe depression.
Ketamine, a popular psychedelic club drug known on the streets as “Special K,” may lead scientists straight to a miracle cure for treating severe depression.

Dennis Hartman, a Seattle business executive, lived a life of chronic depression: he’d endured 25 years of therapy and tried 18 antidepressants and mood stabilizers, but nothing seemed to help. He told the Washington Post that the clinical trial at the National Institute of Mental Health (NIMH) in Bethesda was going to be his last attempt at salvation — and the trial ended up changing his life.

The discovery of the rapid antidepressant effects of the NMDAR antagonist ketamine is arguably the most important advance in the field of psychiatry in the past half century. A single administration of ketamine elicits fast (in as little as half an hour) and sustained antidepressant effects both in humans and in animal models of depression. It also has a fast metabolic turnover rate, with a half-life of three hours. This rapid ‘hit-and-go’ temporal profile suggests that ketamine is likely to act on a system that has ongoing activity with open NMDAR channels.

It all started with ketamine. To some, vets mainly, it’s a horse tranquilizer. To others, a party drug. To those with severe clinical depression, a potential, literal, life-saver. A dose of ketamine can rapidly dull the symptoms of depression, providing immediate relief for those crippled by the darkest thoughts. And while ketamine does not work for everyone, it seems to work in many people who are untouched by standard antidepressant drugs.

Ketamine could then be our best lead in the hunt for depression. For if we search for where ketamine affects the brain, and for how it affects the brain, we will get vital clues to the cause of depression. And so to a long-lasting effective treatment. Two studies just published in Nature used precisely this trick, and spectacularly uncovered not just compelling evidence of the tiny brain region to target, but exactly what goes wrong in it to create depression — that some neurons are, literally, depressed...

A growing series of clinical trials and case series now suggest that ketamine—originally used as an anesthetic agent—potentially offers an exciting new treatment option for severe depression. Increasing numbers of studies show that ketamine can provide prompt relief for many depressed patients, including those with severe treatment-refractory depression. Although the effects of a single treatment are commonly short-lived, multiple infusion protocols may offer sustained relief. The uniquely rapid onset of antidepressant action raises the potential for ketamine use in a variety of clinical situations, including the prevention or shortening of hospital stays, the treatment of acute suicidal ideation, and the facilitation of medication crossovers. Ketamine, in combination with other multimodal treatment approaches, including psychotherapy, may further augment response effect and duration. Promises of efficacy have led to increasingly unbridled use to treat a variety of psychiatric disorders, with diverse approaches and treatment environments, despite inadequate data demonstrating the true clinical efficacy and safety of the various protocols or a thorough understanding of mechanisms of action. This article briefly reviews the history of ketamine’s development as a potential antidepressant, current hypotheses related to its mechanisms of action, and existing evidence for its safety and efficacy with a focus on clinicians’ interests.