The National Institute of Mental Health Highlights Ketamine for Depression

The National Institute of Mental Health (NIMH) issued a highlight on ketamine for treating depression.

The most commonly used antidepressants are largely variations on a theme; they increase the supply within synapses of a class of neurotransmitters believed to play a role in depression. While these drugs relieve depression for some, there is a weeks-long delay before they take effect, and some people with “treatment-resistant” depression do not respond at all.

The delay in effectiveness has suggested to scientists that the medication-induced changes in neurotransmitters are several steps away from processes more central to the root cause of depression. One possibility for a more proximal mechanism is glutamate, the primary excitatory, or activating, neurotransmitter in the brain. Preliminary studies suggested that inhibitors of glutamate could have antidepressant-like effects, and in a seminal clinical trial, the drug ketamine—which dampens glutamate signaling—lifted depression in as little as 2 hours in people with treatment-resistant depression.34

The discovery of rapidly acting antidepressants has transformed our expectations—we now look for treatments that will work in 6 hours rather than 6 weeks. But ketamine has some disadvantages; it has to be administered intravenously, the effects are transient, and it has side effects that require careful monitoring. However, results from clinical studies have confirmed the potential of the glutamate pathway as a target for the development of new antidepressants. Continuing research with ketamine has provided information on biomarkers that could be used to predict who will respond to treatment.35 Clinical studies are also testing analogs of ketamine in an effort to develop glutamate inhibitors without ketamine’s side effects that can then be used in the clinic.36 Ketamine may also have potential for treating other mental illnesses; for example, a preliminary clinical trial reported that ketamine reduced the severity of symptoms in patients with PTSD. 37  Investigation of the role of glutamate signaling in other illnesses may provide the impetus to develop novel therapies based on this pathway.

Left: Change in the 21-item Hamilton Depression Rating Scale (HDRS) following ketamine or placebo treatment.
Right: Proportion of responders showing a 50 percent improvement on the HDRS following ketamine or placebo treatment.34

Source: Carlos Zarate, M.D., Experimental Therapeutics and Pathophysiology Branch, NIMH

One of the imperatives of clinical research going forward will be to demonstrate whether the ability of a compound to interact with a specific brain target is related to some measurable change in brain or behavioral activity that, in turn, can be associated with relief of symptoms. In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities—which lasted up to 14 days.38 Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s RDoC project, which calls for the study of functions—such as the ability to seek out and experience rewards—and their related brain systems that may identify subgroups of patients with common underlying dysfunctions that cut across traditional diagnostic categories.

The ketamine story shows that in some instances, a strong and repeatable clinical outcome stemming from a hypothesis about a specific molecular target (e.g., a glutamate receptor) can open up new arenas for basic research to explain the mechanisms of treatment response; basic studies can, in turn, provide data leading to improved treatments directed at that mechanism. A continuing focus on specific mechanisms will not only provide information on the potential of test compounds as depression medications, but will also help us understand which targets in the brain are worth aiming at in the quest for new therapies.

If you or someone you know is depressed, please make an appointment to see if you are a good candidate for ketamine.  Dr. Ashraf Hanna is located in Clearwater, FL and is one of the leading experts in IV ketamine therapy.  Dr. Hanna is a licensed anesthesiologist and Director of Pain Management at the Florida Spine Institute.  He has performed thousands of infusions and patients travel from all over the world to benefit from his expertise. If you want to learn more, visit his website and listen to his patient testimonies. You won’t be disappointed!  What are you waiting for?  Make an appointment today!

IV Ketamine Shows Promise in Clinical Trial with Depressed Teens

Researchers from the University of Minnesota and The Mayo Clinic found that ketamine caused an average decrease of 42% on the Children’s Depression Rating Scale(CDRS)—the most widely used rating scale in research trials for assessing the severity of depression and change in depressive symptoms among adolescents. The study recruited adolescents, 12-18 years of age, with treatment-resistant depression (TRD; failure to respond to two previous antidepressant trials). The teens were administered intravenous ketamine (0.5 mg/kg) by infusion six times over two weeks.

The study reported that the average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response (defined as >50% reduction in CDRS-R). Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. The ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Interestingly, higher dose was a significant predictor of treatment response.

“Adolescence is a key time period for emergence of depression and represents an opportune and critical developmental window for intervention to prevent negative outcomes,” the authors wrote in the study.

“Unfortunately, about 40% of adolescents do not respond to their first intervention and only half of non-responders respond to the second treatment,” they said. “Because standard interventions require prolonged periods (e.g., weeks to months) to assess efficacy, serial treatment failures allow illness progression, which in turn worsens the outcome. Hence, novel treatment strategies to address treatment-resistant depression in adolescents are urgently needed.”

The authors concluded that their results demonstrate the potential role for ketamine in treating adolescents with TRD. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose.

If you or someone you know is depressed, please make an appointment to see if you are a good candidate for ketamine.  Dr. Ashraf Hanna is located in Clearwater, FL and is one of the leading experts in IV ketamine therapy.  Dr. Hanna is a licensed anesthesiologist and Director of Pain Management at the Florida Spine Institute.  He has performed thousands of infusions and patients travel from all over the world to benefit from his expertise. If you want to learn more, visit his website and listen to his patient testimonies. You won’t be disappointed!  What are you waiting for?  Make an appointment today!

Yale study found no safety issues with long-term ketamine treatment

Researchers at Yale published a new study titled “Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital” in Clinical Psychiatry.  In late 2014, Yale began providing ketamine as an off-label therapy on a case-by-case basis for patients who could not participate in research protocols.  The authors observed 54 patients that received IV ketamine infusion for the treatment of severe and treatment-resistant mood disorders such as depression.

“Ketamine is being used as an off-label treatment for depression by an increasing number of providers, yet there is very little long-term data on patients who have received ketamine for more than just a few weeks,” Samuel T. Wilkinson, MD,from the department of psychiatry, Yale School of Medicine and Yale Psychiatric Hospital, told Healio Psychiatry.

The Yale researchers studied the acute and longer-term outcomes in this patient population. Importantly, a subset of patients (n=14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks.  The researchers found no evidence of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subset of long-term ketamine patients.  They also reported that the infusions were generally well-tolerated.

Although this study population was relatively small, limiting the conclusions that can be drawn, this is still an important first step in establishing the long-term safety of ketamine for the treatment of a myriad of diseases that it’s being used to treat.

If you or someone you know is depressed, please make an appointment to see if you are a good candidate for ketamine.  Dr. Ashraf Hanna is located in Clearwater, FL and is one of the leading experts in IV ketamine therapy.  Dr. Hanna is a licensed anesthesiologist and Director of Pain Management at the Florida Spine Institute.  He has performed thousands of infusions and patients travel from all over the world to benefit from his expertise. If you want to learn more, visit his website and listen to his patient testimonies. You won’t be disappointed!  What are you waiting for?  Make an appointment today!

Treating Chronic Pain With Ketamine

Treating Chronic Pain With Ketamine

Treating Chronic Pain With Ketamine


By Christine Lin, Epoch Times

NEW YORK—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.

Dr. Glen Z. Brooks, who runs a ketamine infusion clinic in New York, first offers an initial session to see if the patient responds. If it’s positive, Brooks recommends a series of six more treatments over the next eight days, either consecutively or every other day. Following that, the patient may return for single treatments for maintenance as needed. Typically, doctors charge $200 to $1,000 for each session.

Brooks, trained as an anesthesiologist, treats patients by referral only.

From March 2012, his practice was offering anesthesia-assisted opiate detox. It was during this time he discovered ketamine’s benefits on pain.

“Some of my patients were addicted to pain medications because they were having problems with chronic pain,” he said. “I noticed that if during their eight-hour detox procedure I added ketamine into the infusion, there were often dramatic improvements on their chronic pain following detox.”

In September 2012, he changed his practice over to ketamine therapy entirely, and sees patients with treatment-resistant depression and neuropathic pain.

“It stops the transmission of pain from the body to the spine and to the brain, and gives the system the chance to reboot,” said Brooks.

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

Ketamine: Reinventing Chronic Pain Management

Ketamine: Reinventing Chronic Pain Management

Ketamine: Reinventing Chronic Pain Management



Author: Jeannette Y. Wick, RPh, MBA, FASCP

For patients who respond poorly or incompletely to opioids, ketamine may be the answer. In the middle of the past century, phencyclidine hydrochloride—called PCP or angel dust on the street—was developed to be a safe, effective anesthetic that did not cause cardiovascular and respiratory depression. However, its propensity to cause convulsions at high doses and long-lasting psychoactive side effects during emergence from anesthesia destroyed its potential.

Ketamine—a PCP derivative—was synthesized in 1963 and was tested on 20 prison volunteers in 1965. One-tenth as potent as PCP, ketamine was intended to induce anesthesia like PCP, but with greater specificity and fewer side effects.

.1 The FDA approved it in 1970, and its widespread use in the Vietnam conflict theater catapulted its popularity

.2 Today, ketamine is used less and less in the operating suite

.3 Although ketamine’s psychomimetic side effects are milder than those of PCP, they can be problematic (Table 12-10).

Screen Shot 2015-06-09 at 4.02.20 PM

Recreational abuse has dogged ketamine since its approval. Abusers have injected, inhaled, and smoked ketamine, revealing characteristics of the drug that would otherwise remain unknown. Researchers hypothesize that abusers may develop tolerance because ketamine induces liver enzymes.11 Abusers rarely experience withdrawal, instead reporting a sensation called the K-hole—a constellation of visual hallucinations, dissociation, and out-of-body, and sometimes, near-death experiences. Heavy, prolonged ketamine use can cause cognitive and psychological impairment.4,12-15

Up to one-third of chronic ketamine abusers develop dose-dependent urinary tract symptoms within weeks to years: lower urinary tract irritation (vesicopathy), hydroureter, and hemorrhagic or ulcerative cystitis.13,16,17

The symptom etiology remains unclear, but may be direct toxic damage, immune system activation, or the effect of unknown bacteria.16,18

Long-term complications include hepatotoxicity (jaundice, itching, or elevated liver enzyme levels, especially in alcoholic patients) and/or cholangiopathy.19,20

Some long-term abusers develop corneal edema.21

These complications reverse after cessation of ketamine use.17,20,21

Clinically, the most common side effects of ketamine are inebriation, mental alteration, headache, hypertension, and altered liver enzymes.22

Newer, cleaner drugs or biologics are replacing ketamine in the operative suite. Yet ketamine is finding a new place in clinical therapy. Ketamine, an N-methyl-D-aspartate (NMDA)–receptor antagonist, is becoming an option for perioperative pain management among patients with opioid tolerance, acute hyperalgesia, and chronic neuropathic pain.1

NMDA Receptors

NMDA receptors are 1 of 3 glutamategated ion receptors. Gated by a magnesium ion, they normally open only briefly to allow calcium ions and other cations to enter the cell. Calcium activates second- messenger systems, causing neuronal hyperactivity.1,22-24 NMDA receptors may be involved in neuronal survival and maturation, synaptic plasticity, and memory. Abnormal NMDA function may cause neurologic disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, depression, epilepsy, multiple sclerosis, Parkinson’s disease, and schizophrenia.25 Unrelenting NMDA receptor excitation allows continuous calcium influx into the cell and creates hyperexcitability. This presents clinically as opioid tolerance, hyperalgesia, and allodynia.22,26,27

Ketamine is the most potent clinically available, uncompetitive, open-channel NMDA-receptor blocker (it only works if the receptor is activated and the channel is open). Ketamine depresses the thalamus and limbic systems, preventing central nervous system centers from receiving or processing sensory input. This creates anesthesia, analgesia, and amnesia, and sometimes unpleasant psychomimetic effects or emergence phenomena.23,28,29

Sympathetic cardiovascular stimulation caused by ketamine is unique among intravenous anesthetics: it inhibits neuronal catecholamine reuptake, thereby increasing heart rate, cardiac output, and systemic and pulmonary blood pressure.30,31 Theoretically, ketamine use should be avoided in patients with prolonged QT syndrome.32 Ketamine inhibits neuronal serotonin reuptake, causing an emesis that is reversed by 5-HT–receptor blockers.33,34

What Route?

To minimize adverse events associated with ketamine use, researchers are examining the use of administration routes other than intravenous. Oral ketamine, as an injectable liquid or a compounded product, is subject to hepatic first-pass metabolism and is less effective than parenteral doses. It also lacks a clear dose-response relationship.22,35 Some study results suggest that the oral route leads to few side effects.36 Topical formulations of ketamine or ketamine with other potential analgesics has been used for managing several painful conditions (eg, pelvic pain, pruritus) with mixed results.22,37-39

Managing Pain

Ketamine use in pain management evolved from its perioperative use. Perioperative pain is expected, but may have physical or psychological consequences that delay rehabilitation and prolong hospitalization.1 Most surgeons use opioids to treat postoperative pain and supplement with regional anesthesia, other analgesics, and adjuvant agents as needed.1,23,40 Some patients respond poorly or incompletely to opioids; ketamine may help these patients.26,27,41

In low doses, NMDA-receptor antagonists can provide analgesia and circumvent opioid-related tolerance, hyperalgesia, and allodynia.10,23,40 Randomized, placebo-controlled, double-blind clinical trials (RCTs) have found that perioperative subanesthetic doses of ketamine added to opioid analgesia improved pain scores and reduced opioid consumption by approximately 30% to 50%. Ketamine was given as an intermittent low-dose intravenous bolus or a continuous infusion. It reduced opioid-related nausea and vomiting and added no additional significant adverse effects.42,43

Ketamine can also be given with morphine patient-controlled analgesia, contributing a morphine-sparing effect. Patients with chronic neuropathic pain, opioid dependence or tolerance, and acute hyperalgesia seem to benefit more.42,43 Low-dose ketamine administered before the surgical incision can lead to better analgesia for 24 hours after surgery.1 Most studies report no significant increase in psychomimetic adverse effects when ketamine is added to morphine.42,43

Sickle Cell Crisis and Chronic Noncancer Pain

Acute sickle cell disease creates severe pain with a neuropathic element. Several published guidelines recommend using opioids as first-line treatment, but some patients are unresponsive to even high opioid doses. Rapidly escalating opioid doses may induce acute tolerance and opioid-induced hyperalgesia.29,44 Case studies (but no RCTs) indicate that adding a low-dose ketamine infusion to opioids can improve pain in sickle cell disease.44 Usually, NMDA receptors activate continually only after a severe, sustained painful stimulus allows sufficient glutamate release. This is why ketamine may be useful as an adjuvant in several types of chronic central and peripheral neuropathic pain (Table 223,45,46).

Several of ketamine’s properties may prevent chronic pain from developing:

Dampening of nociception
Prevention or attenuation of hyperalgesia, allodynia, and tolerance
Attenuating central sensitization and windup phenomenon from repeated noxious stimuli when previously nonpainful stimuli become exaggerated and painful23,40

Clinicians have used short-term subanesthetic doses of ketamine to treat neuropathic pain.45 Scheduled infusions over several days can improve pain scores in patients with chronic pain; a few studies report pain relief persisting for weeks following treatment, indicating that ketamine may be disease modifying.46

Cancer Pain

Limited but increasing data support ketamine use in refractory cancer pain. Adding a small dose of ketamine to opioid therapy in a patient with opioid tolerance, called burst therapy, can improve pain management.12,47 Patients on highdose opioids whose cancer pain has a neuropathic component may respond to oral ketamine.48 Adding a small dose of ketamine to patient-controlled morphine seems to improve pain management, and some researchers are testing a ketamine mouthwash for mucositis.49,50


Large, well-designed RCTs are needed to confirm the analgesic role of ketamine. Most studies suggest, and experts believe, that ketamine use should be reserved for patients in whom opioids, anticonvulsants, or antidepressants have failed.3,36 Because pain management is an off-label use for ketamine, clinicians should consult with field experts for dosing recommendations.

Ms. Wick is a visiting professor at the University of Connecticut.
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