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Ketamine’s Efficacy Validated in Major Refractory Depression

Caroline Cassels (Medscape.com)

Ketamine is a rapid, effective treatment for patients with treatment-resistant depression, new research shows.

The study showed that a single intravenous dose of ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, improved depression in 64% of patients within 24 hours of administration vs 28% of patients who received the anesthetic midazolam.

“Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression,” the investigators, with first author James Murrough, MD, assistant professor of psychiatry and neuroscience and associate director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai, in New York City, write.

Reported in April 2013 at the Anxiety and Depression Association of America 33rd Annual Conference and covered by Medscape Medical News at that time, the results of 2-site, parallel-arm, randomized placebo-controlled study were published online August 28 in the American Journal of Psychiatry.

Promise of New Therapies

The study, which the researchers note is the largest to date to test the antidepressant effects of ketamine, included 73 participants with treatment-resistant major depression. Patients were randomly assigned in a 2:1 ratio to receive IV ketamine (n = 47) or midazolam (n = 25).

The study’s primary outcome was change in depression severity 24 hours after drug administration, as measured by the Montgomery-Ǻsberg Depression Rating Scale (MADRS).

Depression scores were not significantly different between treatment groups at 7 days.The researchers report that the likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% confidence interval, 1.21 – 4.14), with response rates of 64% and 28%, respectively.

Side effects associated with ketamine infusion included dissociative symptoms immediately following administration in 8 patients (17%). However, these side effects resolved by 2 hours postinfusion. In addition, for 2 patients, ketamine infusion was terminated due to significant changes in blood pressure.

The researchers note that more research is needed to identify strategies to prolong and maintain ketamine’s initial antidepressant response and to determine the drug’s long-term safety profile.

In an accompanying editorial, A. John Rush, MD, Duke–National University of Singapore Graduate Medical School in Singapore, writes that study does not validate a new treatment but rather points to a promising lead for new therapeutic development.

“While insufficient to recommend a wholesale change in practice presently, these results certainly provide substantial hope for patients with treatment-resistant depression, insight into the biology of this condition, and a major obligation by clinician scientists and funding agencies to answer this next set of important clinical questions for our patients with refractory depression,” Dr. Rush writes.

 

KETAMINE AND DEPRESSION

by Alexis King

DEPRESSION: Depression can come in many forms, but when the symptoms begin to interfere with people’s daily lives these feelings become an illness. Signs of depression include feelings of hopelessness or guilt, loss of interest in activities that used to be enjoyable, thoughts of suicide, and many more. Some people have minor bouts of depression, but major depressive disorder can be disabling. Other forms of depression are postpartum depression, which occurs after giving birth, and seasonal affective disorder, which comes on during the winter months due to lack of natural sunlight. Medications and psychotherapy may help to alleviate depression symptoms, but are ineffective in helping some individuals.

KETAMINE: The drug ketamine was first developed in 1963 to be used as an anesthetic in humans as well as animals. When used for medical purposes, ketamine comes as a liquid that is injected into patients and is chemically similar to PCP. Although doctors and veterinarians continue to administer the drug as an anesthetic, ketamine is also used recreationally as a “street drug.” Typically snorted or ingested in powder form, ketamine has been known to cause dream-like states and hallucinations. When taken in large amounts ketamine can cause an effect called the “K-hole” in which people experience an inescapable, often terrifying out-of-body experience.

MEDICAL BREAKTHROUGH: A new study, conducted by researchers at the Baylor College of Medicine in Houston and Mount Sinai School of Medicine in New York, shows that the experimental party drug, ketamine, can alleviate depression symptoms in just hours. The drug was shown to quickly reduce depression in participants after just one 40-minute IV dose. Most medications available today can take days, if not weeks, to reduce symptoms. The drug also has long-lasting results. After one week, 46 percent of the ketamine-assigned patients still reported reduced depression symptoms after taking the ketamine, compared to 18 percent in the placebo group. Although the ketamine has obvious benefits, it is still a hallucinogenic drug that can be very dangerous if not used under the supervision of a trained medical doctor.

For more information about the services we offer, please visit us at South Shore Neuropsychiatric Center.

TREATING CHRONIC PAIN WITH KETAMINE

By Christine Lin, Epoch Times | August 8, 2013

As human beings, we instinctively avoid pain—the sting of nettles, the burn of a hotplate, the pinching of door hinges. Pain is useful because it communicates immediate danger and helps us keep out of it. However, some pain is chronic, as neuropathic pain often is.

Neuropathic pain derives from the central nervous system or peripheral nervous system. It is pain that comes from the nerves, as opposed to common muscular aches and arthritic pain. Sometimes it is triggered by traumatic accidents.

In support forums, patients suffering from neuropathic pain describe their symptoms as “burning all over,” “shooting pains in the arms and legs,” “agony,” and “unbearable.” Many of them recount their experiences in seeking relief “frustrating,” that they’ve “tried everything,” or that “not one doctor can give me an answer.”

Neuropathic pain, as a broad category of conditions that include neuralgia, phantom limb syndrome, complex regional pain syndrome (CRPS), and central pain syndrome, is a little-understood realm in medicine. We don’t always know its causes. And current treatment methods are mediocre at best.

Even its occurrence rate among the general population is hard to discern.

In 2008, a study of neuropathic pain incidences in the Dutch population found it has an annual incidence of almost 1 percent of the general population and affects women and middle-aged persons more often.

A 2005 survey of three U.K. cities puts the rate at 8 percent, while a 2006 one conducted in France came up with 5 percent.

Chronic pain affects more than day-to-day functioning. A study last year published in the Journal of Neuroscience found that people with chronic back pain or CRPS have smaller hippocampi than healthy people.

The hippocampus plays a crucial role in processing information, memory, and spatial navigation.

CURRENT TREATMENTS HIT-OR-MISS

While researchers are slowly forming a better idea of what causes neuropathic pain, the research has been hard to translate into medical practice, leaving many patients feeling hopeless. Part of the reason is that there are likely a variety of causes that depend on the patient’s history of injury, lifestyle, and drug history.

Tricyclic antidepressants and anticonvulsants are the common, first-line drugs used to treat neuropathic pain.

According to a 2005 study, tricyclic antidepressants will give relief to one in every two to three patients with peripheral neuropathic pain, which is superior to serotonin noradrenaline reuptake inhibitors (SNRIs), which are successful in one in every four to five, and selective serotonin reuptake inhibitors (SSRIs), good for one in every seven patients.

Anticonvulsants have not been found to be more effective than tricyclic antidepressants with an efficacy rate about the same as that of SNRIs.

EMERGING TREATMENT

Patients who fail to find relief may have a new treatment option to turn to.

A 2006 study in the American Journal of Therapeutics found that 85 percent of neuropathic pain patients who underwent outpatient ketamine infusion saw improvements in their conditions. Just over half of the study participants reported continued relief one month after discontinuing treatment.

Known more popularly for its abuse as a club drug, ketamine has been recognized and used for several decades as an anesthetic. It works to stop the transmission of pain by blocking N-methyl-D-aspartate (NMDA) receptors. Recent research has identified hyperactivity of these receptors as a possible factor in generating neuropathic pain.

Few medical establishments in the United States administer ketamine infusions. While it does not cure neuropathic pain conditions, treatment can put the patient into remission long enough to give the nervous system a chance to repair itself.

Despite the drug itself being inexpensive, the cost of ketamine infusion runs the gamut, from $200 to $2,000 per session in outpatient clinics.

Very rarely, hospitals offer it as an in-patient option, which, factoring in all overhead, runs an average of $25,000 for a five-day course of treatment, according to American RSD Hope, an association of neuropathic pain sufferers. However, a Web search revealed that none of the country’s largest medical institutions currently offers the therapy as more than part of clinical research.

Outpatient options are more cost-effective but take several hours a day, for a week or so.

Of CRPS patients, he said, 80 percent see dramatic reduction in their pain with lasting improvement, and 20 percent do not.

For more information about our services please visit us at South Shore Neuropsychiatric Center.

DRUGS TO LIFT DEPRESSION IN HOURS RATHER THAN WEEKS

By Andrea Petersen

The hunt is on for a faster-acting, more effective antidepressant.

Current treatments for depression, including drugs like Prozac and Celexa, often take a month or more to give patients relief—and they don’t work for everyone. Now, researchers and several pharmaceutical companies are testing medications that early studies are showing can lift mood in just a few days or even within a couple of hours.

“You can control seizures and control hypertension within minutes and hours,” says Carlos A. Zarate, chief of the experimental therapeutics and pathophysiology branch in the intramural research program at the National Institute of Mental Health and a leading researcher in the search for new antidepressant medications. “That is what we should aim for [with depression],” he says.

Some of the fast-acting treatments being studied, such as ketamine and scopolamine, use existing medications in a new way. Ketamine has been used in higher doses as an anesthetic for decades. Small doses of scopolamine delivered via skin patch are used to treat motion sickness. AstraZeneca PLC, the London-based drug company, Naurex Inc., a pharmaceutical firm in Evanston, Ill., and Cerecor Inc., a Baltimore-based biotechnology company, are all developing new drugs for depression that act similarly to ketamine.

It will likely be at least a couple of years before any of the new drugs come to market, since they first need further clinical trials and Food and Drug Administration approval. Some doctors are already using ketamine off label with depressed patients.

Ann Wroth has struggled with depression for more than 30 years and has tried eight different medications. Each time she has a relapse and tries a new medication, she says, it takes at least three to four weeks before she sees any benefit. “The waiting period is very difficult. You’re still in pain. [You think] ‘I’m taking this pill, ‘why isn’t it helping,’ ” says the 53-year-old who trains volunteers at the National Alliance on Mental Illness, an Arlington, Va.-based mental health education and advocacy group.

In a study published in the American Journal of Psychiatry in 2006 of nearly 3,000 patients taking the popular antidepressant citalopram (brand name Celexa) for up to 14 weeks, only about one-third achieved remission from their depression. (About half of the participants responded to the drug, meaning their scores on a survey assessing depression improved by at least 50% during the trial.) For those who did achieve remission or had a response, it generally took about eight weeks of being on the medication.

The new fast-acting drugs act on the brain in an entirely different way than the current popular antidepressants. Ketamine and the new compounds from AstraZeneca and Naurex all act on the brain’s N-methyl-D-aspartate (NMDA) receptors, which are involved in learning and memory. These receptors interact with the neurotransmitter glutamate, the levels of which seem to be out of balance in depression.

Scientists believe glutamate is a much more direct target for depression than serotonin, a neurotransmitter affected by selective serotonin reuptake inhibitor (SSRI) drugs like Prozac and Paxil. The SSRIs’ more indirect method of action is likely the reason why there is a lag time before patients feel relief from depressive symptoms, says Ronald S. Duman, professor of psychiatry and neurobiology at the Yale University School of Medicine in New Haven, Conn.

In a small but groundbreaking study published in 2006 in the Archives of General Psychiatry, 17 people with major depression who had failed to get adequate relief from at least two other antidepressants were given a single injection of ketamine. About one-third of patients went into remission and 71% had a response. Patients began to feel better within two hours and the beneficial effects lasted about a week.

But ketamine has side effects including hallucinations and other “dissociative” feelings during and for a bit after an intravenous infusion. “People may see trails of light, they may feel a bit foggy,” says Dr. Zarate, lead author of the study. Indeed, Ketamine is sometimes abused as a street drug called “special K.” There is also concern that repeated doses of ketamine could be harmful to the brain.

AstraZeneca and Naurex say their new compounds deliver the rapid benefits of ketamine without the disturbing side effects because they act differently on the NMDA receptor. Naurex said the main side effects in a Phase IIa study of its GLYX-13 compound with 116 people with depression were headache and sleepiness, similar to the effects of a placebo saline injection. Patients began feeling relief of their depression symptoms within two hours and the effects lasted at least one week.

Naurex is in the middle of another study with 400 patients. It expects to apply to the FDA for approval of GLYX-13 in early 2016, says Ronald M. Burch, the company’s chief medical officer. While GLYX-13 will likely be indicated for patients who failed to benefit from conventional antidepressants first, the company is also beginning to study an oral version of the drug. That formulation could be used as a first treatment option for depression, Dr. Burch says.

AstraZeneca is in the middle of a second Phase IIb trial of its AZD6765 compound, testing it in 282 people.

Pierre Blier, a professor of psychiatry at the University of Ottawa in Canada has given ketamine to about 25 patients in the last 18 months. “I use it in my severely ill patients who are on medications already,” he says. He only uses it with patients who don’t have a history of addiction, he says, and who he knows well. “When it works it is so striking,” he says.

Some psychiatrists believe ketamine or drugs like it will be helpful in emergency rooms with patients who are actively suicidal. Richard Shelton, a professor in the department of psychiatry and behavioral neurobiology at the University of Alabama at Birmingham has been conducting a small study and has used ketamine this way in 16 people.

“People come in urgently wanting to kill themselves,” he says. After a low-dose ketamine infusion, “the sense of urgency goes away.”