Edward Fruitman, MD
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Hewlett, NY 11557
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Anxiety

TMS Can Help Treat Root Causes of Depression & Anxiety

Dr. Edward Fruitman, Medical Director of South Shore Neuropsychiatric Center offers innovative genetically based treatment options for Depression and Anxiety. At South Shore Neuropsychiatric Center we offer a simple test that gives insight into our patients’ specific genetic profile which enables Dr. Fruitman to optimize medication regimen and/or offer alternative treatment options.

Recent studies suggest that early life experiences in combination with genetic predispositions are major contributors to treatment resistant anxiety and depression.  The amygdala is a region of the brain responsible for emotion regulation while the prefrontal cortex (PFC) is responsible for emotion processing. Fear inducing cues increase amygdala activity and cause the physiological responses to anxiety. The PFC regulates the amygdala effect by inhibiting autonomic and endocrine responses to stressors. In essence, the PFC controls the extent of an emotional response. Individuals that experience heightened anxiety and depressive symptoms are shown to have an inability to control and habituate responses to stressors.  Studies suggest that genetic factors may contribute to this effect. Researchers found that in “subjects carrying a substituted methionine in the BDNF gene, fear doesn’t extinguish as readily in response to repeated nonthreatening cues; in those with a valine, it extinguishes more easily. Using neuroimaging, the authors showed that polymorphism carriers exhibited more amygdala and less PFC activity with subsequent cue presentations.”  In these individuals the PFC is dormant and individuals may not respond to psychotherapy or medication.

Transcranial Magnetic Stimulation Therapy (TMS) is a noninvasive treatment option for individuals suffering from treatment resistant anxiety and depression.  TMS stimulates the PFC using noninvasive magnetic energy, which over time provides relief to depression and anxiety symptoms. Dr. Edward Fruitman is the pioneer provider of Transcranial Magnetic Stimulation (TMS) Therapy in the Five Towns area. Dr. Fruitman has successfully treated patients suffering from anxiety and depression with TMS since 2010.

PROBLEM: ADDED COST FOR MEDICAL PATIENTS WITH TREATMENT RESISTANT MAJOR DEPRESSION SOLUTION: TRANSCRANIAL MAGNETIC STIMULATION?

Behavioral Healthcare/ December 4, 2013

By Alison Knopf

neurostar-infoTranscranial Magnetic Stimulation (TMS) may be the best way to help patients with treatment-resistant major depression (TRMD) – people who have tried antidepressants at least once for the appropriate amount of time on the appropriate dose, according to Pete Mumma, Administrative Director of the Behavioral Health Service Line in the Department of Psychiatry at Lancaster General Health in Lancaster, Pennsylvania. But that doesn’t mean it’s easy to “sell” the TMS device to financial people in your institution.

Here’s how Mumma did it: 9.1 percent of the population has depression, and .05 percent has TRMD. These people are “superutilizers,” who consume 18 percent of a health system’s uncompensated or undercompensated spending. “It’s unsustainable,” he said. “We expect people who have extreme needs to be treated in pathway models that don’t meet their needs – what will we do with these patients, not just from a mental health perspective, but from a total medical perspective?”

For example, an individual with TRMD who also has cardiac disease or cancer is going to be very complicated to treat. “Any medical provider who is helping patients with TRMD is going to bump up against some or all of their issues,” said Mumma. Symptoms such as lack of energy, lack of concentration, and sleep problems create further distractions for the patient, he said. The recommendations of the cardiologist or oncologist won’t go as far as they would if the patient didn’t have depression.

The impact of mental health problems on physical treatment is more relevant now than it was in the past because of the way health systems are being reimbursed, said Mumma, citing in particular the penalty for readmissions within 30 days. If a patient fails cardiac treatment – perhaps because he didn’t exercise, something that is notably difficult for people with depression – and needs to be readmitted, that’s a ding to the hospital’s bottom line. “So cardiologists and every other doctor wants to make sure they eliminate barriers to good outcomes,” he said. Mental problems that make it difficult to follow through with physician recommendations are suddenly seen as very important – a good thing for both patients and the health care system.

“We can spend a little money up front to treat the depression, and the patient’s cardiac care goes farther, faster,” said Mumma.

The treatment

Typically, patients start with a daily course of treatment, which takes about 37 minutes. This would go on for four to six weeks. The treatment is painless and requires no sedation. Once the initial course is done, some patients may come back for a maintenance treatment. The treating provider will determine the exact treatment protocol and any maintenance needed.

Medications

The first line of treatment for depression is medication, but people with TRMD are patients for whom medication isn’t working. On the system side, the clinical benefit is important, but on the patient side, it’s crucial. “The tragic thing is these patients aren’t getting better,” said Mumma of TRMD.

Doing depression care differently – what Mumma is suggesting is avoiding the “shotgun approach” that most depression patients who have tried one medication after another have experienced. At Lancaster, before selecting a medication, the psychiatry department does “pharmacogenetic” testing via a cheek swab to at least narrow down the type of medication to try in the first place. “But many patients get agent after agent, and have had no other options over their lifetime.” Now, at least patients who have failed one course of medication with an appropriate dose and duration have another option.

“Through medications, we’re trying to light up some parts of the brain and quiet others,” said Mumma. That’s the same thing that TMS does – the magnet near the head “reaches deep into the amygdala, which scientists think is responsible for mood,” he said. “Instead of washing the brain with chemicals, this seems to isolate the problem.” Many patients continue to take medications while getting TMS but find they can reduce their medications over time, he added.

Another issue is the cost of medications. Abilify, the medication used for treatment-resistant major depression, is very expensive, said Mumma. “The health plan might be paying more than $1,000 per month” for Abilify, he said. “Add to that the costs of Celexa or other medications, plus the medication management.”

Tracking medical costs

Mumma also has scrutinized the literature, finding that one study showed that the most costly expense to employers was depression, at a cost of more than $350,000 per thousand employees. That isn’t only medical costs, of course, but aggregated costs of medical treatment, pharmacy, absenteeism, and “presenteeism” – in which employees are still at work but unable to function. “If we were to do depression care differently, that’s a huge savings,” said Mumma.

Patients paying

In clinical trials, suicidality was four times higher in the placebo group than the TMS group, said Mumma. (In the clinical trials, TMS was compared to sham TMS, not compared to medication.)

Major depression is a devastating disease for people who don’t get better, and 40 percent of the patients experience remission, said Mumma, who is not compensated by Neuronetics.

The big question is whether TMS is going to be as effective as electroconvulsive therapy (ECT), said Mumma. Clearly TMS is much more appealing to patients. “ECT is scary as hell, and it has ugly side effects like memory loss,” he said. ECT is effective, but many studies are showing comparable results for people with TMS, said Mumma.

“Nobody’s using the word, ‘cure,’” said Mumma. But TMS is different from medications, he said. TMS is non-medication based treatment, so there are no drug-drug interactions. “It’s difficult to get off of antidepressants once you get on, and antidepressants are basically a band-aid for a problem – just symptom improvement, not managing the illness.”  TMS does allow patients to return to functionality with fewer side effects than medication, said Mumma.

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.

 

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION OFFERS RELIEF FROM DEPRESSION

Umesh Isalkar, TNN Jul 28, 2013

Rakesh used to feel low. Soon he lost interest in his job. He took to alcohol to feel better and things kept going downhill after his wife walked out. When he approached doctor for treatment of depression, he had already spent two years in depression.

Today, Rakesh has almost recovered and leading a normal and productive life. Thanks to a new treatment modality called repetitive transcranial magnetic stimulation (rTMS). Rakesh is just one of many suffering from depression and one of the few who have had his depression treated with rTMS Therapy.

According to WHO ( World Health Organization) report depression is going to be second leading cause for disability. The problem however is not the illness but lack of awareness and stigma attached to it.

“Depression if not treated can last for more than a year. Treatment is necessary as depression can lead to professional, family, financial, and physical health related complications including suicide,” said psychiatrist Swapnil Deshmukh of Shreeyash Hospital who has treated Rakesh with rTMS.

Various types of treatment modalities are available depending on severity of illness including cognitive behavioural therapy (CBT), medicine, electro convulsive therapy (ECT), and latest – rTMS ( re-petitive Transcranial magnetic stimulation). All these are standard, well proved and accepted worldwide -FDA approved treatment modalities.

“Around 20% of cases are mild and can be treated with CBT itself but remaining requires medications in addition to counselling. Around 30 to 40% of depression cases can be severe, resistant to treatment.

“rTMS is a recent treatment modality in depression and other psychiatric illness in which magnetic waves can directly stimulate affected- less functioning brain areas non-invasively. It is considered to be safest, non-medicine dependent, cost effective treatment modality getting very popular in west. Combination of both rTMS and medication and therapy work best,” Deshmukh said.

For more information about our TMS services please contact us at South Shore Neuropsychiatric Center (516)295-4867

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.

NeuroStar Patient Experience Video

NeuroStar Patient Experience Video

For more information on TMS Therapy or to schedule your free initial consultation with Dr. Fruitman, please contact us at South Shore Neuropsychiatric Center, (516)295-4867.

NEW APPROACH TO DEPRESSION

By RONI CARYN RABIN

Martha Rhodes experienced her first bout of depression at 13. By her late 50s, she had taken just about every antidepressant there is, including Zoloft, Lexapro and Paxil — which did the trick for many years, but had side effects — then Effexor, Lamictal, Seroquel and Abilify.

After a suicide attempt in 2009, she tried something radically different: transcranial magnetic stimulation, or TMS, a treatment in which magnetic pulses are used to stimulate parts of the brain believed to be involved in mood regulation. Unlike electroconvulsive or shock therapy, which is also used to treat stubborn depression, TMS does not generally produce seizures.

Every day, she spent just over half an hour in a chair with a powerful magnet affixed to the front left side of her head. After four weeks, “I woke up and something was different,” said Mrs. Rhodes, who wrote a book, “3,000 Pulses Later” describing the treatment. “I felt lighter. I didn’t wake up in the morning and wish I were dead.”

For Mrs. Rhodes, 63, a former advertising executive in Danbury, Conn., TMS treatment was transformative, and she no longer needs antidepressants. But there are still many questions about just how many severely depressed patients respond to TMS, which requires daily office visits for several weeks, costs thousands of dollars and is often not covered by insurance.

For the therapy, patients sit in a doctor’s office with a large magnet pressed to the left side of their heads. The idea is that a pulsed magnetic field, similar to that used in M.R.I.’s, creates an electrical current in the surface of the brain that “resets” the patient’s mood regulatory system.

TMS is approved specifically for patients whose depression does not respond to antidepressants or who cannot tolerate the drugs’ side effects, which include weight gain and loss of sex drive. Many of these patients are desperate for alternative treatments, but it’s not certain that TMS can provide the help they need.

“While it’s fairly clear that TMS is effective in some percentage of patients with major depressive disorder, it’s still not very easy to know in advance who those patients are,” said Dr. Steven J. Zalcman, the head of the clinical neuroscience research branch of the National Institute of Mental Health.

The American Psychiatric Association’s practice guidelines say that TMS confers “relatively small to moderate benefits,” and the results of clinical trials have been decidedly mixed. “The glass is half full or half empty, depending on where you’re coming from,” said Dr. Mark S. George, a professor at the Medical University of South Carolina in Charleston.

Dr. George was an investigator in the first independent, randomized trial of repetitive TMS to treat resistant depression. That study found that nearly three times as many patients went into remission after TMS treatment, compared with those receiving a placebo, the absolute numbers were still small.

A newer variation of the treatment, deep TMS, developed by an Israeli company called Brainsway and approved by the Food and Drug Administration this year, brought a higher response rate in a randomized trial: 30 percent of 233 patients in the trial achieved remission, compared with 14.5 percent of the control group.

The device targets deeper regions of the brain, like the nucleus accumbens, which plays a pivotal role in the reward circuit of the brain, company officials say.

In industry-financed studies that allowed subjects to continue their antidepressant medications while undergoing TMS treatment, which experts say is a more likely situation in the real world, response rates were significantly higher than in the randomized trial conducted by Dr. George. A recent study, as yet unpublished and also financed by equipment makers, that followed patients for a year reported the treatment had a lasting effect, with nearly half the patients maintaining improvement for 12 months.

An advantage of TMS treatment is that it is not invasive and, unlike medication, appears to have few side effects, just occasional discomfort or mild pain in the scalp at the site of the treatment, or headaches. Few patients drop out of treatment because of the pain, however.

Long-term effects are not known, but TMS does not take a toll on memory and cognition, as electroconvulsive therapy can. In rare cases it may cause seizures.

In a demonstration of TMS a 55-year-old woman who asked not to be identified to preserve her privacy, sat in a chair while a small, heavy magnet held by a mechanical arm was positioned over the prefrontal cortex of the brain.

There was no anesthesia or sedation. The patient was allowed to read or watch TV, just not fall asleep. Nodding off seems unlikely, however, since the treatment makes a strident woodpecker-like rat-a-tat sound that lasts for four seconds, followed by 26 seconds of silence before resuming. A daily session lasts about 37 minutes.

The patient, who has had a full course of TMS and is now receiving occasional treatments, said the therapy had pulled her out of severe long-term depression.

“I didn’t even realize I’d slipped,” she said. “I wish I’d done this a long time ago.”

TMS FOR RESISTANT DEPRESSION: LONG-TERM RESULTS ARE IN

MedScape- Caroline Cassels

May 24, 2013

SAN FRANCISCO — Transcranial magnetic stimulation (TMS) appears to offer long-term efficacy in patients with treatment-resistant major depressive disorder (TR-MDD), new research shows.

Presented here at the American Psychiatric Association’s 2013 Annual Meeting, the multicenter, longitudinal, naturalistic, observational study showed that acute TMS induced “statistically and clinically meaningful response and remission” in patients with TR-MDD during the acute phase, and that the results were maintained at 52 weeks.

“This is the first study to examine 12-month outcomes of TMS in a large dataset in a real-life setting. We have data on 257 patients that got all the way through the long-term follow-up, and we found that 68% improved and 45% had complete remission at 1 year follow-up,” study investigator Linda L. Carpenter, MD, professor, Department of Psychiatry and Human Behavior, Brown University School of Medicine, and chief, Mood Disorders Program, Butler Hospital, in Providence, Rhode Island, told Medscape Medical News.

“I think this will really be impressive for confirming the long-term durability of this effect to potential payers. This is exciting times for psychiatrists and patients, who have a new treatment option to pursue,” she added.

Previous research has shown that TMS is a safe and effective acute treatment option for patients with TR-MDD. However, the long-term efficacy and durability of the treatment in this patient population were unclear.

To assess the changes in depressive symptoms and functional capacity across the duration of acute and long-term follow-up of TMS treatment, the investigators studied 307 depressed patients who were part of a prospective multicenter observational clinical trial examining the utilization and outcomes of the NeuroStar TMS Therapy System (Neuronetics Inc, Malvern, Pennsylvania).

Study participants had a primary diagnosis of unipolar, nonpsychotic major depressive disorder and had failed to receive benefit from prior antidepressant treatment. The mean age of the participants was 48.6 ± 14.2 years, and 66.8% were women.

The study’s primary outcomes included Clinical Global Impressions–Severity of Illness Scale (CGI-S), Patient Health Questionnaire (PHQ-9), and the Self-Rated Inventory for Depression Symptomatology (IDS-SR).

All patients initially received the standard simulation protocol (120% of motor threshold, 10-Hz cycles of 4 seconds of active stimulation followed by 26 seconds of no stimulation for a total of 3000 pulses per treatment session), but this could change to meet patient needs. Treatment was received daily for a period of 4 to 6 weeks.

Real-world Study

Of the total study population, 264 patients (62%) from 42 clinical practices achieved symptomatic improvement, and 41% reported complete remission with acute treatment.

Of these individuals, 257 entered a 12-month long-term follow-up phase of the study, in which they were tapered off of the acute treatment regimen and were observed for 52 weeks.

Outcome measures were obtained at 3, 6, 9, and 12 months. Concurrent medication use and TMS reintroduction for recurrent symptoms were recorded and summarized during the long-term follow-up.

At 12 months, 68% of patients achieved symptomatic improvement, and 45% reported complete remission. Maintenance of benefit was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS reintroduction for symptom recurrence.

The researchers report that compared with baseline, there was a statistically significant reduction in mean CGI-S, PHQ-9, and IDS-SR total scores at the end of acute treatment, which was sustained throughout the 52-week follow-up period.

“The durability of NeuroStar TMS Therapy demonstrated by this robust, real-world study is remarkable, as it’s not typical to see long-term benefit in patients who have treatment-resistant forms of depression,” study investigator Philip Janicak, MD, professor of psychiatry, Rush University Medical College, and medical director of the Rush Psychiatric Clinical Research Center, in Chicago, said in a statement.

“Great News”

Asked by Medscape Medical News for independent comment on the study, Mark George, MD, professor of psychiatry, radiology, and neurosciences and director of the Medical University of South Carolina Center for Advanced Imaging Research as well as the Brain Stimulation Laboratory in Charleston, said that the study is good news for clinicians and patients alike.

Dr. George’s group was the first to publish a study on TMS and depression in 1994, and he has been actively investigating the technology since that time.

He also led a large National Institutes of Health study, published in 2010, showing that repetitive daily TMS produced statistically significant and clinically meaningful antidepressant effects compared with sham treatment in patients with TR-MDD.

“This is a very important and exciting study. Several prior studies have shown that prefrontal rTMS works to treat depression acutely. Until this study, we have had only limited information about how well these patients do a year after completing a course of TMS. Long-term data following remission produced by medications or electroconvulsive therapy [ECT] in these treatment-resistant patients have been disappointing, with only about 13% being still remitted a year later.

“For example, over half of patients who remit with ECT are ill again 6 months later. Thus, having 45% in remission a full year later is very, very encouraging that rTMS is perhaps changing the underlying pathological circuitry associated with depression and producing a more stable remission than the other treatments.

“This is great news for our field and for the millions of patients who suffer from depression and do not respond well to medications,” Dr. George added.

The American Psychiatric Association’s 2013 Annual Meeting. Abstract NR12-5. Presented May 21, 2013.

TMS FOR RESISTANT DEPRESSION: LONG-TERM RESULTS ARE IN

 

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.”

TREATMENT RESISTANT DEPRESSION STUDY

Study on Neuron Regeneration for Treatment Resistant Depression

Overview: The standard of care for clinical depression has significant limitations: traditional drugs that focus on monoamine neurotransmitters can take several weeks to be effective, and many patients never respond to any form of treatment. Several clinical trials have demonstrated strikingly better outcomes using the anesthetic ketamine to treat depression. Notably, a single application can have rapid and lasting antidepressant effects in patients who do not respond to other treatments. Because ketamine is an antagonist of NMDA-type glutamate receptors, research is focused on the role of glutamate neurotransmission in depression and on drug development that targets the glutamatergic system. The March 25, 2013, meeting of the Academy’s Biochemical Pharmacology Discussion Group, Treatment-resistant Depression: Glutamate, Stress Hormones, and their Role in the Regeneration of Neurons, presented this new research and the avenues it is opening for the treatment of depression.

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