Ketamine as a Treatment for Post-traumatic Stress Disorder

City:		New York
State:		New York
Zip Code:		10029

Conditions:		Stress Disorders, Post-Traumatic - PTSD - Depression - Anxiety Disorder
Purpose:		The objective of the proposed study is to test if a single IV dose of ketamine (0.5 mg/kg) decreases symptoms of PTSD.
Study Summary:		PTSD is a debilitating anxiety disorder characterized by intrusive re-experiences of the traumatic events, avoidance of situations and stimuli that could serve as reminders of these events, and feeling jumpy or easily startled. Patients with PTSD are often also depressed, and many have significant memory impairments. Existing drug treatments are unsuccessful in a majority of patients, especially in those with combat-related PTSD. Our aim is to test the effectiveness of a potential new drug for PTSD, ketamine. For many years, intravenous ketamine has been extensively used for anesthesia. More recently, using doses lower than those used in anesthesia, a single ketamine infusion was shown to rapidly reduce depressed mood as well as anxiety in patients with severe depression. Some clinical evidence of potential efficacy in depressed patients with co-morbid PTSD also exists. Adverse effects in these studies have been limited to feeling intoxicated and having increased blood pressure during the infusion. In the present study, we expect a single ketamine infusion to reduce core PTSD symptoms. In addition, in those patients with PTSD who are depressed, we expect ketamine to reduce depressed mood. Finally, ketamine is known to impair memory function temporarily. We will also test if the extent of ketamine-induced memory impairment during the infusion can predict how well people do after the infusion. Forty patients with PTSD (with and without combat-related trauma histories) will be tested, using a design that will compare the effectiveness of intravenous ketamine to that of midazolam, another anesthetic drug without any known long-term effects on anxiety, depressed mood, and memory function. If ketamine is found to have the expected effects, future studies may explore additional benefits of repeated infusions and / or alternatives to intravenous drug administration. Our study may contribute to improved function of patients with PTSD by providing a new means to rapidly treat their debilitating symptoms.
Criteria:		Inclusion Criteria: - Men or women, 21-55 years of age; - Participants must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign a written informed consent document; - Participants must fulfill DSM-IV criteria for current civilian or combat-related PTSD, based on clinical assessment by a study psychiatrist and on the CAPS (score must be at least 50 at screening and prior to each infusion - this is done to ensure at least moderate severity and to safeguard against high placebo response rates); additionally, clinicians will use clinical judgment to assess if patients are symptomatic enough to receive each infusion - Women must be using a medically accepted reliable means of contraception (if using an oral contraceptive medication, they must also be using a barrier contraceptive) or not be of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year); - Women of childbearing potential must have a negative pregnancy test at screening and pre-infusion; - Participants must be able to identify a family member, physician, or friend (i.e. someone who knows them well) who will participate in a Treatment Contract (and e.g. contact the study physician on their behalf in case manic symptoms or suicidal thoughts develop). Exclusion Criteria: - Women who plan to become pregnant, are pregnant or are breast-feeding (because the medical risk of using ketamine during pregnancy and breast-feeding is unknown); - Serious, unstable medical illnesses such as hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease (including gastro-esophageal reflux disease, obstructive sleep apnea, history of difficulty with airway management during previous anesthetics, ischemic heart disease and uncontrolled hypertension, and history of severe head injury); - Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG; - Patients with uncorrected hypothyroidism or hyperthyroidism; - Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first infusion day; - Use of evidence-based individual psychotherapy (such as prolonged exposure) and other non-pharmacological treatments during the study; - Histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome; - History of one or more seizures without a clear and resolved etiology; - History of (hypo)mania; - Past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including schizophrenia or schizoaffective disorder; - Drug or alcohol abuse or dependence within the preceding 3 months (given that this might otherwise contribute to their symptoms, however, a rather narrow time period was chosen such as to allow participation by individuals with a history of substance abuse or dependence problems that could be secondary to their PTSD, and to more closely approximate patients seen in real-world settings); - Previous recreational use of ketamine or PCP; - Current diagnosis of bulimia nervosa or anorexia nervosa; - Diagnosis of schizotypal or antisocial personality disorder (since these are known to reduce the possibility of study completion; other Axis II diagnoses will be allowed); - Patients judged clinically to be at serious and imminent suicidal or homicidal risk. - A blood pressure of one reading over 160/90 or two separate readings over 140/90 at screen or baseline visits.
NCT ID:		NCT00749203
Primary Contact:		Principal Investigator Dennis Charney, MD Mount Sinai School of Medicine Julia Morgan Phone: 212-241-7906 Email: julia.morgan@mssm.edu
Backup Contact:		Adriana Feder, MD Phone: 212-659-9145
Location Contact:		New York, New York 10029 United States There is no listed contact information for this specific location. Site Status: Recruiting

Study: Ketamine holds promise for PTSD treatment

Study: Ketamine holds promise for PTSD treatment

http://www.nepsy.com/articles/leading-stories/study-ketamine-holds-promise-for-ptsd-treatment/

Ketamine has already shown effectiveness in lifting symptoms of deep depression. Researchers at the Yale School of Medicine, the VA Connecticut Healthcare System, Mount Sinai School of Medicine and other research institutions are pursuing more studies to learn more about how ketamine can work within hours to alleviate symptoms

“I don’t think any drug is a miracle drug, but I think that ketamine has produced some very exciting data,” says John H. Krystal, M.D., chair of Yale’s department of psychiatry and chief of psychiatry at Yale-New Haven Hospital.

A Yale pilot study found subjects with severe depression given a low dose of ketamine showed a reduction of symptoms within four hours and were, Krystal says, “by the next morning, basically in remission.”

Compare that to SSRI antidepressants like Paxil, which can take four to six weeks before improvement is evident.

Krystal began working with ketamine in 1989 to study schizophrenia. It was first developed for veterinary medicine before being adopted for battlefield surgery because it does not suppress breathing unlike other anesthetics. Ketamine blocks the n-methyl-D-aspartic acid (NMDA) receptor on the glutamate pathway in the brain involved in memory and mood regulation. Researchers think ketamine’s antidepressant effect comes from restoring synapse connections that may have deteriorated under stress and depression.

Other studies have shown similar results, including a 2006 study by the National Institute of Mental Health in which 70 percent of participants experienced rapid symptom relief with one intravenous dose of ketamine.

A 2008 U.S. Army Institute of Surgical Research study found that Operation Iraqi Freedom/Operation Enduring Freedom service members in treatment for burns who received ketamine during surgery had a lower prevalence of PTSD (27 percent) than those who did not (46 percent). The results occurred despite having larger burns, more serious injuries, more surgeries and spending more time in the ICU.

Mount Sinai School of Medicine is currently conducting a study to investigate the effectiveness of ketamine in PTSD patients led by the school’s dean, Dennis S. Charney, M.D., formerly of Yale and a mentor to Krystal. Charney, through a school spokesman, declined to discuss the study while still underway. He indicated he would be able grant an interview sometime in the fall.

Ketamine is sold as a generic under the brand name Ketalar. Large doses can be dangerously debilitating and produce hallucinations. As a popular nightclub street drug, ketamine is known as Special K. It is listed as a Schedule III drug under the U.S. Controlled Substances Act.

Krystal says ketamine has been studied in such a small population so far and ultimately thinks scientists will learn how it works to develop another, safer antidepressant.

“I think it’s been an interesting and useful tool to identify novel ways to treat depression,” he says.

By Janine Weisman

Posted in Articles, Leading Stories | 1 Comment »

Yale: 'Magic Antidepressant May Hold Promise for PTSD

Yale: 'Magic' Antidepressant May Hold Promise For PTSD

June 03, 2012|By LISA CHEDEKEL, Conn. Health I-Team Writer, The Hartford Courant

Now, a number of drug companies, as well as academic institutions, have seized on the glutamate system to test new antidepressant medications. One of the drugs being tested by Yale researchers is Riluzole, which is FDA-approved to treat Lou Gehrig's disease but has shown benefits in treating depression. Pfizer, AstraZeneca and other companies are testing other drugs that modulate glutamate.

Ketamine, which is sold as a generic and under the brand names Ketalar and Ketaject by Pfizer, is the subject of multiple trials.

"As of right now, the initial studies are promising in concept. But in terms of bringing ketamine to clinical practice, we still have some important unanswered questions," such as whether repeat doses work over time, Sanacora said. On the other hand, he said, if glutamate-altering drugs are shown to be effective, "they could be available fairly quickly. We could be looking at a new class of drugs in the next five years."

Chasing Glutamate In Alcoholism, Suicidal Behavior

Ketamine also has drawn interest from researchers studying alcohol addiction, largely because of findings indicating that the drug's negative effects are blunted, and positive effects more pronounced, in people with a family history of alcoholism.

Researchers at Yale and the West Haven VA are now conducting a study to gauge the effects of ketamine on mood and alcohol consumption in patients with both depression and alcohol dependence.

"Our hypothesis is that it might work particularly well on depression" in patients with both conditions, and that it also might "reduce cravings," said Dr. Ismene Petrakis, chief of psychiatry for the VA Connecticut Healthcare System and principal investigator on the study. "The thinking is that alcohol is a little like ketamine, so if you drink for many years and you're blocking your NMDA receptors, your body might compensate."

A prior study led by Petrakis indicated that underlying alterations in NMDA receptors may make some people less likely to get the "warning signs" to stop heavy drinking, the study suggested.

"If there's some underlying problem with NMDA receptors [in people with alcoholism], ketamine might be something that can address that," Petrakis said.

Krystal, of Yale, who began studying ketamine in relation to schizophrenia in 1989, said some hospitals and psychiatric facilities are now administering the drug on a "compassionate use" basis, when all other antidepressant treatments have failed. In Houston, for example, doctors affiliated with the Ben Taub General Hospital and the Baylor College of Medicine are giving ketamine to severely ill patients who have not responded to any other treatment.

A pilot study by Yale researchers found that a low dose of ketamine "rapidly reduced" suicidal thoughts in 20 patients who showed up in the emergency room with severe depression and suicidal ideation. A second study, by NIMH researchers, had similar results.

But more important than the drug itself, ketamine researchers said, is understanding more about the way it works.

"I think it is a great drug to tell us about the [glutamate] mechanism, but we have to wrestle with whether it's the best drug for depression," especially given dosing questions and the risks of abuse, Krystal said. "We view it still mostly as a research tool."

Charney said the ketamine PTSD study was underway, and it was too early to discuss results. Just last month, in another indication that the two FDA-approved drugs for treating PTSD were lacking, the Army announced plans to launch a multiyear study to evaluate the effectiveness of a range of medications that are being prescribed "off-label" to treat PTSD.

Krystal and other researchers already have found fault with one off-label drug: In a study published last summer, they determined that the antipsychotic risperidone, widely prescribed for PTSD at veterans hospitals, did not reduce the overall severity of military-related PTSD. The research has raised broader questions about the practice of prescribing atypical antipsychotics in PTSD treatment.

On the other hand, recent research has shown potential benefits of a drug called D-cycloserine (Seromycin), which is a partial blocker of the NMDA receptor. One study found that D-cycloserine reduced fear and anxiety in patients who were receiving exposure therapy, a technique used to treat PTSD.

As more veterans return home with PTSD, researchers say science needs to catch up — quickly. Krystal and others are hopeful that glutamate might be a new frontier.

"One of the challenges we have in the PTSD field is that there has been so little study of medications," Krystal said. "As prevalent as [the disorder] is, there is just not much research out there. That has to change."

This story was reported under a partnership with the Connecticut Health I-Team (www.c-hit.org).

Ketamine: New Potential as Rapid PTSD Treatment NOT JUST FOR DEPRESSION ANYMORE?

http://www.medscape.com/viewarticle/823760

Ketamine: New Potential as Rapid PTSD Treatment

NOT JUST FOR DEPRESSION ANYMORE?

Caroline Cassels

April 17, 2014

 

The first evidence from a randomized clinical trial that the anesthetic agent ketamine may provide rapid symptom reduction in patients with chronic posttraumatic stress disorder (PTSD) when delivered intravenously has been published.

An N-methyl-D-asparate (NMDA) glutamate receptor, ketamine has made headlines in recent years because several trials conducted by investigators at the Icahn School of Medicine at Mount Sinai in New York City have shown that it delivers a rapid antidepressant effect when delivered intravenously and, most recently, intranasally in spray form.

In this latest proof-of-concept study, researchers led by Adriana Feder, MD, found that intravenous (IV) infusion of ketamine hydrochloride (0.5 mg/kg) was associated with significant and rapid reduction of PTSD symptom severity compared with an active control agent.

"These findings may lead to novel approaches in the treatment of chronic PTSD ― a condition that affects a broad spectrum of adults in the United States and beyond, including victims of sexual assault, war veterans, those who have witnessed catastrophic events such as the September 11 terror attacks, and others," Dr. Feder, associate professor of psychiatry, Icahn School of Medicine at Mount Sinai, said in a release.

"However, this should be viewed as a proof-of-concept study. Additionally, longer-term clinical trials with ketamine will be required to determine if it will be a clinically useful treatment for PTSD," she added.

The study was published online April 16 inJAMA Psychiatry.

Fast-Acting Antidepressant

Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of PTSD, which is chronic and disabling, the investigators note.

They add that there is a growing body of evidence showing that glutamate plays a major role in mediating stress response, the formation of traumatic memories, and PTSD pathophysiology.

An agent that has been used for anesthesia at 2 mg/kg and analgesia at subanesthetic doses, ketamine has a good safety track record and is superior to other anesthetic agents because it reliably preserves breathing reflexes.

The researchers note there have been no randomized clinical trials examining the effect of ketamine in chronic PTSD. The few that have been conducted were either retrospective or nonrandomized.

Building on previous research showing that ketamine is effective in treatment-resistant depression, the investigators conducted a proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, another anesthetic agent that has pharmacokinetic parameters and nonspecific behavioral effects that are similar to ketamine.

"In recent years, we and others have shown that ketamine could often counter the symptoms of depression in treatment-resistant cases. In the present study, we hypothesized that ketamine would be associated with significantly greater reduction in core PTSD symptom levels 24 hours after a single IV infusion, and that it would also improve comorbid depressive symptoms in patients diagnosed with PTSD," principal investigator Dennis Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, said in a statement.

The study included 41 patients between the ages of 18 and 55 years with a primary diagnosis of PTSD and a score of at least 50 on the Clinician-Administered PTSD Scale (CAPS). Study participants were free of concomitant psychotropic medications for 2 weeks prior to randomization and for the duration of the study.

The study's primary outcome was change in PTSD symptom severity 24 hours after infusion, using the Impact of Event Scale–Revised (IES-R). Secondary outcome measures included the Montgomery- Åsberg Depression Rating Scale (MADRS), the Quick Inventor of Depressive Symptomatology, Self-Report (QIDS-SR), and the Clinical Global Impression–Severity (CGI-S) and –Improvement (CGI-I) scales administered at 24 hours, 48 hours, 72 hours, and 7 days after infusion.

In addition, adverse events were monitored with the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.

Rapid Symptom Reduction

For each procedure day, patients were assigned to receive a single IV infusion of ketamine hydrochloride or midazolam administered during a period of 40 minutes.

The order of infusions was randomly assigned, and administrations occurred 2 weeks apart.

Ratings were administered at preinfusion baseline and 24 hours (day 1) after infusion (before patients were discharged from the hospital), 48 hours (day 2) after infusion, 72 hours (day 3) after infusion, and 7 days (day 7) after infusion.

Study results revealed that ketamine infusions were associated with a "significant and rapid reduction in PTSD symptom severity compared with midazolam 24 hours after infusion" (mean difference in IES-R score, 12.7; 95% confidence interval, 2.5 - 22.8; P = .02).

The investigators also report that there was a greater reduction of PTSD symptoms following treatment with ketamine in both crossover and first-period analyses that remained significant after adjusting for baseline and 24-hour depressive symptom severity.

The researchers also found that ketamine was associated with a reduction in comorbid depressive symptom severity and improvement in overall clinical presentation.

In addition, they report that the drug was "generally well tolerated without clinically significant persistent dissociative symptoms."

"Our results provide the first evidence that a single dose of IV ketamine was associated with rapid reduction of core PTSD symptoms and reduction in comorbid depressive symptoms…," the authors write.

They add that the results need to be replicated in other trials and that this research should "examine the efficacy and safety of ketamine beyond a single infusion for patients with chronic PTSD, explore the use of ketamine anesthesia to prevent the emergence of PTSD symptoms in surgical patients with a history of trauma, investigate the mechanisms of ketamine action, and identify pretreatment predictors of response to this intervention."

This study was funded by the Department of the Army – US Navy Medical Research Acquisition Activity. Dr. Charney and Dr. Feder have been named as inventors on a patent application covering the use of ketamine for the treatment of PTSD.

JAMA Psychiatry. Published online April 16, 2014. Abstract

Ketamine for the treatment of depression

http://www.ncbi.nlm.nih.gov/m/pubmed/23413455/?i=8&from=oral%20ketamine%20depression

Ketamine for the treatment of depression.

Journal of Psychosocial Nursing and Mental Health Services. 2013 Jan;51(1):11-4.

       

Ketamine (Ketalar®) is an anesthetic agent derived fro the hallucinogenic drug phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate receptors and also binds to opioid mu and sigma receptors. Ketamine is being intensively investigated as an antidepressant therapy. To date, five short-term controlled studies and other open-label studies in patients with unipolar or bipolar depression have demonstrated that intravenous ketamine is safe and has a rapid and profound short-term effect on depressive symptoms, including suicidal thoughts, even among patients considered treatment-resistant to standard medications or electroconvulsive therapy. Before ketamine can be incorporated into clinical practice, however, its long-term safety and effectiveness need to be evaluated. Although the effectiveness of alternative routes of ketamine administration (i.e., oral, intranasal, or intramuscular) needs to be determined, intravenous ketamine could be conceptualized as a clinic-based procedural therapy for treatment resistant forms of depression.

PMID

 23413455 [PubMed - indexed for MEDLINE]

Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial

Oral Ketamine & Treatment of Depression

Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial

 Show all

Journal

J             Of Palliative  Med. 2013 Aug;16(8):958-65. doi: 10.1089/jpm.2012.0617. Epub 2013 Jun 27.

Affiliation

Abstract

BACKGROUND: Depression and anxiety are prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Ketamine has many properties that make it an interesting candidate for rapidly treating depression and anxiety in patients receiving hospice care. To test this hypothesis, a 28-day, open-label, proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability, potential efficacy, and time to potential efficacy in treating depression and anxiety in patients receiving hospice care.

METHODS: In this open-label study, 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride (0.5 mg/kg) over a 28-day period. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS), which was used to rate overall depression and anxiety symptoms at baseline, and on days 3, 7, 14, 21, and 28.

RESULTS: Over the 28-day trial there was significant improvement in both depressive symptoms (F5,35=8.03, p=0.002, η(2)=0.534) and symptoms of anxiety (F5,35=14.275, p<0.001, η(2)=0.67) for the eight subjects that completed the trial. One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression. A significant response in depressive symptoms occurred by day 14 for depression (mean Δ=3.5, d=1.14, 95% CI=1.09-5.9, p=0.01) and day 3 for anxiety (mean Δ=2.4, d=0.67, 95% CI=1.0-3.7, p=0.004). These improvements remained significant through day 28 for both depression (mean Δ=4.0, d=1.34, 95% CI=2.3-5.9, p=0.001) and anxiety (mean Δ=6.09, d=1.34, 95% CI=3.6-8.6, p<0.001). Side effects were rare, the most common being diarrhea, trouble sleeping, and trouble sitting still.

CONCLUSIONS: Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events. The response rate for depression is similar to those found with IV ketamine; however, the time to response is more protracted. The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject populations.

PMID

 23805864 [PubMed - indexed for MEDLINE]

PMCID

 PMC3717203 [Available on 2014/8/1]

Full text: Mary Ann Liebert, Inc.

Ketamine: A Possible Role for Patients Who Are Running Out of Options?

May 02, 2011 | Bipolar Disorder, Dissociative Identity Disorder, Major Depressive Disorder, Neuropsychiatry, Alcohol Abuse

By Arline Kaplan

- See more at: http://www.psychiatrictimes.com/articles/ketamine-possible-role-patients-who-are-running-out-options#sthash.lHPbNBqe.dpuf

Encouraged by recent studies showing that a single IV infusion of ketamine can have antidepressant effects within hours in patients with treatment-resistant major depression (TRD) or bipolar depression, a psychiatric team at the University of California, San Diego (UCSD) Medical Center has begun offering ketamine infusions to patients who “are running out of options.”

“We are not studying ketamine per se,” said David Feifel, MD, PhD, associate professor of psychiatry and neurosciences at UCSD and director of the Medical Center’s Neuropsychiatry and Behavioral Medicine Service. Rather, he and his team have developed a protocol of IV ketamine for severely depressed patients who have unsuccessfully run the gamut of medications and possibly ECT. It is one of several approaches offered in their Treatment Refractory Program.

According to Feifel, patients are informed that ketamine is not approved for this use, that insurance does not cover its use, and that optimal use of ketamine in depression is still being studied. Patients are also warned that if they do respond to ketamine, its effects are temporary, and that staff will work with them on how to maintain a treatment response.

What the research shows

The impetus for ketamine research stems from the need for rapid-response antidepressants. Many patients do not benefit from standard antidepressants; others may take weeks or months to respond, said Carlos Zarate Jr, MD, chief of the Experimental Therapeutics and Pathophysiology Branch of the Division of the Intramural Research Program at the NIMH and lead investigator on several ketamine studies.

The Sequenced Treatment Alternatives to Relieve Depression Trial (STAR*D), for example, showed that only a third of patients with major depressive disorder achieved remission (ie, minimal/no residual symptoms) after 1 adequate treatment trial with a traditional antidepressant.1

We can rapidly control blood sugar or high blood pressure in a matter of minutes or hours, Zarate said. Similarly, we need interventions that can work rapidly in depressed patients, he added.

Evidence indicates that the glutamatergic system is involved in the pathophysiology and treatment of mood disorders, Zarate said. Earlier studies found altered glutamate levels in serum and cerebrospinal fluid from patients with mood disorders.2 Postmortem studies found altered glutamate levels in diverse brain areas in individuals with mood disorders.3 Ketamine increases the firing rate of glutamatergic neurons and the presynaptic release of glutamate.

Much is known about ketamine, a high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, ac-cording to Zarate. “It is an approved anesthetic that is used worldwide, particularly in ED settings as well as in children, so it has a good track record of safety,” he said. “Using ketamine as an experimental drug, we tested the hypothesis of whether directly going to the NMDA receptor complex target would bring about rapid antidepressant effects, and indeed we found it to be the case,” he said.

The first small, preliminary investigation by Berman and colleagues4 found significant antidepressant effects within 72 hours after ketamine infusion in 7 individuals with TRD. Zarate and coworkers5 subsequently confirmed the rapid antidepressant response with ketamine. Zarate’s team conducted a double-blind, crossover, placebo-controlled study involving 18 patients; those with TRD experienced symptom relief in as little as 2 hours with a single IV dose of ketamine (0.5 mg/kg over 40 minutes).

Of the 17 patients treated with ketamine (1 patient dropped out), 71% met response criteria (50% improvement on 21-item Hamilton Depression Rating Scale) and 29% met remission criteria the day following the infusion. The response was sustained for at least 1 week in 35% of patients.

“We have conducted a series of other studies,” Zarate told Psychiatric Times. Some looked at bipolar depression, suicidal ideation, and predictors of response.

His team recently completed a placebo-controlled study in treatment-resistant bipolar depression with 18 subjects.6 “After a single IV infusion, we found very rapid antidepressant effects starting within 1 hour, which lasted most of the week,” Zarate said. In the randomized, placebo-controlled, double-blind, crossover, add-on study, 12 of 17 (71%) patients responded to ketamine; 3 patients had a response that lasted 2 weeks or more.

Ketamine also has an anti-suicidal effect, which is critically important given that individuals with mood disorders are often at risk for suicide within the first month of starting a medication, Zarate said. Adding to the challenge, he said, is that in the past decade there has been a significant increase in ED visits for suicidal ideation or attempts. Suicides have occurred even in inpatient psychiatric units and have become an urgent issue for the US military.

At the Mount Sinai School of Medicine in New York, researchers found that a single subanesthetic dose of IV ketamine had rapid effects (1 day after infusion) on suicidal ideation in patients with TRD and that acute improvements in suicidality could be sustained through re-peated ketamine infusions.7

DiazGranados and others,8 part of Zarate’s team, showed that in patients with major depressive disor-der who had significant suicidal ideation, improvement occurred within 40 minutes of a ketamine infusion. Predictors of response to IV ketamine, Zarate said, include a family history of alcohol dependence,9,10 increased pretreatment rostral anterior cingulate cortex activity,11 and anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task.12

In the next few months, Zarate said his team will start a ketamine mechanism of action study (http://patientinfo.nimh.nih.gov). “We will be looking at people who have failed only one adequate antidepressant trial in their lifetime, so it will be a much less treatment refractory group,” he said. “We will be studying several hundred people with unipolar depression or bipolar depression and using novel technologies, including multimodal brain imaging, polysomnography, genetics, and cognitive measures.”

The reason for this extensive battery, according to Zarate, is to better understand how ketamine works and to tease out who might respond and what might be the markers for predicting response.

“We hope to be able to identify signatures of rapid response which then could be utilized to develop other similar types of compounds,” Zarate said.

The team’s research has also prompted investigation of ketamine for other mental disorders. “We have not published these data yet, but ketamine has significant anti-anxiety effects,” said Zarate. People with certain symptoms of anxiety or trauma and those with obsessive symptom profiles appear to benefit from the ketamine infusion, he noted.

The NIH’s Web site (www.clinicaltrials.gov) indicates that some studies of ketamine in obsessive-compulsive disorder and PTSD, and as augmentation of ECT for severe major depression, are under way. Other researchers are looking at the feasibility of repeated-dose IV ketamine for acute management of TRD. In one recent study, symptoms relapsed, on average, 19 days after the sixth ketamine infusion; however, 1 patient remained antidepressant-free with minimal symptoms for more than 3 months.13

Asked about the notoriety ketamine gained as the abusable club drug known as “K,” Zarate said that during its infusion, ketamine can cause dissociative side effects. He noted that his team has safely administered ketamine to more than 100 patients in a controlled setting. We are trying to determine “which subunit of the NMDA receptor is responsible for side effects and which is responsible for improvement,” he said, explaining that there are major efforts in academia and the pharmaceutical industry to find safer ketamine-like drugs.

Zarate added that his NIMH program is “geared to looking at rapid treatments.” He hopes that having ketamine and scopolamine, which temporarily block the muscarinic cholinergic receptor, “will serve as a great model to better understand what mechanism is involved in the beginning of an antidepressant response. We hope this will lead to the development of treatments with a rapid onset of action.”

Clinical practice

As regards his clinical work with ketamine at UCSD, Dr Feifel had this to say:

You have patients who have been severely depressed for years and nothing has helped. Both patients and their providers wonder whether there is any possibility that patients will ever be free of their depression. Part of our goal is to see whether their nervous system is amenable to turning off depression through some sort of biological intervention, such as ketamine. So if ketamine is able to turn off a patient’s depression, even for one day, you have accomplished something important, whether or not you can maintain it. This is because you have at least given the patient hope . . . that in itself is very significant from a therapeutic perspective.

REFERENCES

References

1. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
2. Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des. 2009;15:1595-1611.
3. Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry. 2007;62:1310-1316.
4. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
5. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
6. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802.
7. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522-526.
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