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  1. source

    Donald says he thought he’d died minutes after ketamine, a popular club drug known as Special K, was infused into his vein at a Sydney hospital in March.

    “I couldn’t see anything except pure white,” recalled the 63-year-old depression suffer, who declined to be identified by his last name. “I thought, ‘oh well, I must have died.’”
    His vision normalized within a couple of hours, he said. So did his mood, giving Donald respite from the debilitating depression that had defied a dozen antidepressants he’d taken over decades.

    The former academic’s experience is part of broader tests to determine whether ketamine, a hallucinogen commonly used to anesthetize horses, can offer a new avenue for relieving the low mood and self-esteem and feelings of hopelessness that plague as many as 121 million people worldwide.

    “This could really be a game-changer,” said James W. Murrough, an assistant professor in the departments of psychiatry and neuroscience at New York’s Mount Sinai School of Medicine, which has several ketamine studies under way. “There is a real need for something that works quickly.”

    Ketamine, used as an anesthetic during the Vietnam War, was deemed revolutionary when it was discovered in the early 1960s just after psilocybin, which gives “magic mushrooms” their mind-altering potential. Research on psychedelic drugs was curtailed after experimentation outside labs led to widespread abuse, said Charles S. Grob, professor of psychiatry at the University of California, Los Angeles.

    “The hallucinogens were really the cutting edge of psychiatric research,” Grob said.
    Now that doctors have a better grasp of how the brain works, they’re realizing their colleagues in the 1950s and early 1960s were on to something. Pharmaceutical companies are interested as well. London-based AstraZeneca and a unit of New Brunswick, N.J.-based Johnson & Johnson have drugs in mid-stage patient studies designed to work in a similar way, but with better results.

    Animal tests show ketamine promotes the growth of brain nerve-cells and their connections that are the cornerstones of learning and memory. Scientists are trying to see if the compound has the same dramatic effect in severely depressed and suicidal people. The research has already shed new light on the biological mechanisms of depression.

    Ketamine may help patients who don’t respond to conventional antidepressants, such as Eli Lilly’s Cymbalta or H. Lundbeck’s Lexapro, which don’t work on about a third of those who try them, says Alana Simorellis, an analyst with Decision Resources Inc. in Waltham, Mass. It may also benefit people who need urgent relief from suicidal tendencies, so long as the drug is given under the supervision of doctors in a hospital, she said.

    Modern antidepressants typically target the serotonin and noradrenaline brain receptor systems. While the drugs take two to six weeks to work on mood and self-esteem, they can improve energy and motivation sooner, giving a suicidal patient greater volition to end their lives, Grob said.

    “There is really no medical intervention for acute suicidality, which is a medical and psychiatric emergency,” said Mount Sinai’s Murrough, who is running a trial to investigate the drug’s potential to prevent suicide. “It’s a huge unmet need.”

    Besides Sydney and New York, ketamine is being investigated for depression at sites in Boston, Houston and Miami, as well as Changzhou, China; Grenoble, France; Geneva, Switzerland; and Aberdeen, Scotland, according to data compiled by Bloomberg.
    Janssen Research & Development, a unit of J&J, is beginning studies in the United States and Europe of a different molecular structure of ketamine, as well as a novel compound targeting the same mechanism of action in patients with depression.

    “We’re really interested in ketamine because of some of the earlier work done in academic medical centers and the effectiveness that it’s shown,” said Greg Panico, a spokesman.
    Some rival drugmakers, including GlaxoSmithKline, the London-based maker of the Paxil and Wellbutrin depression medications, have given up on research in the field.

    Designing medicines that modify the actions of large molecules in the brain is hard, says Clare Stanford, professor of experimental psychopharmacology at University College London, and only real innovation will pay off.

    “If you’re developing something new, it’s got to be really new, otherwise it’s not worth developing,” Stanford said. “It will be too expensive and you won’t be able to recoup the cost.”
    Already sales of existing drugs are falling. Global antidepressant revenue will drop an estimated 24 percent to $8.54 billion by 2020 as bestsellers such as Pfizer’s Effexor and Lilly’s Cymbalta face generic competition, according to Decision Resources. Sales of Lilly’s Prozac alone topped $2.6 billion a year before it lost U.S. patent protection in 2001.

    Ketamine targets brain receptors activated by a transmitter called glutamate that’s important for synapses — the electrical and chemical signaling neurons use to communicate. Their activation in the hippocampus and the cerebral cortex — areas of the brain involved in memory, mood and cognition — are thought to be especially important in treating depression.

    Antidepressants including Prozac also cause changes in synapses, though not as quickly as ketamine, said Murrough. It may be speed that gives ketamine an advantage for depression, which has been linked with alterations and abnormalities in glutamate levels, he said.

    “These effects seem to occur over weeks with standard antidepressants and with ketamine, they occur rapidly,” Murrough said. “What Prozac did in two to four weeks, ketamine in a single dose was doing in one day” in experiments with animal models, he said.

    Brain images of depressed people suggest the condition may be caused by atrophy in the hippocampus. Ketamine increases the growth of new synapses, much like electroconvulsive therapy or ECT, said Colleen Loo, a psychiatrist leading a study of the drug at Sydney’s Black Dog Institute.

    Donald, the patient who thought he’d died on ketamine, is one of five people with treatment-resistant depression recruited so far in Loo’s placebo-controlled study. She wants 35 more to understand the drug’s effects on blood pressure, heart rate, and various psychiatric and neuropsychological measures. A second trial will investigate how its impact could be sustained.
    Donald says his mood improved for as long as two days after receiving ketamine. “On the days of the treatment, I felt quite calm, relaxed and positive,” he said. “I was disappointed that it didn’t have this wonderful, long-lasting effect, but there is definitely something going on there.”

    A positive mood response lasting as long as a few weeks has been observed so far in trial participants, some of whom didn’t respond to ECT, Loo said.
    “The fact that some people who have failed ECT can respond to ketamine is amazing,” she said. “It’s a paradigm shift.”

    Ketamine, with a reputation as a mind-distorting club drug, should be investigated with caution, said M. Margarita Behrens, a scientist at the Salk Institute in La Jolla, Calif. The medicine, whose street name is a play on Kellogg’s Special K breakfast cereal, initially disinhibits brain circuitry, causing over excitement in response to a stimulus.

    The effects are transient and disappear when the drug is eliminated from the system. When taken repetitively, though, ketamine can change the way inhibitory neurons behave, she said.
    It’s possible that ketamine’s antidepressant action derives from this mechanism and that, by disinhibiting the brain, the drug brings a depressive person into a normal state, but a normal person into psychosis, Behrens said.

    “If not used carefully we could end up curing depression with schizophrenia,” she said.

    By Jason Gale, Makiko Kitamura and Allison Connolly, Bloomberg News - Posted July 09, 2012

    Artlicle from Bangor News


  1. SeekingHelp
    This is one of the craziest things I have ever read. Checks and balances need to be continually checked and improved at places like hospitals.
  2. Calliope
    [IMGL="white"]http://www.drugs-forum.com/forum/attachment.php?attachmentid=27842&stc=1&d=1346168610[/IMGL]Ketamine-Induced Optimism: New Hope for the Development of Rapid-Acting Antidepressants
    Athough we have made significant advances in the treatment of mood disorders, studies such as the STAR*D and STEP-BD have made us increasingly aware of the limitations of the effectiveness of our current treatment strategies.1, 2

    Moreover, the fact that the currently existing antidepressant treatments require several weeks to produce a clinically meaningful improvement leads to high rates of discontinuation, extended hospital stays, prolonged suffering—and possibly even increased rates of suicidal behavior.

    A series of studies completed over the past 12 years suggest that a novel class of drugs that directly target the glutamatergic neurotransmitter system may produce rapid and robust antidepressant effects in patients who had previously not responded to the standard monoaminergic antidepressant medications. Here I discuss the clinical studies that demonstrate the antidepressant effect of ketamine and other glutamatergic drugs, review the risks associated with some of these medications, and highlight the many still unanswered questions regarding the treatments. I also present information on several ongoing clinical trials in this area and encourage use of the NIH-sponsored registry of clinical trials, http://clinicaltrials.gov, when treatment options are being considered for patients with treatment-resistant mood disorders.

    Glutamate is by far the most abundant and ubiquitous neurotransmitter in the mammalian CNS (Figure 1). Although it is known to serve as the major excitatory neurotransmitter in the brain, it was only recognized as a true neurotransmitter less than 30 years ago.3 Since that time, accumulated evidence has demonstrated glutamate’s central role in mediating nearly all forms of brain function, including cognition, perception, learning, and emotion. There is increasing evidence that disrupted glutamatergic signaling can contribute to the pathophysiology of a large variety of neuropsychiatric disorders. Preclinical studies are beginning to elucidate the connections between impaired function of glutamatergic synapses and stress-related conditions, such as mood disorders.4

    The earliest evidence that a glutamatergic drug could have antidepressant effects was presented by George Crane in the late 1950s, long before the recognition of glutamate as a neurotransmitter.5 He noted the rapid antidepressant effects of cycloserine—now known to be a partial agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor—when it was used to treat patients with tuberculosis. He specifically remarked on the rapid improvement of insomnia, anorexia, and tension in those patients.

    Although he noted “cycloserine may become a valuable agent in psychopharmacological research considering the fact that its chemical structure and mode of action are different from those of most drugs with psychic effects,” there was little follow-up until the late 1980s, when Phil Skolnick’s laboratory at the NIH began to seriously examine the role of the NMDA receptor in the pathology of depression and as a target for antidepressant drug development.6 A series of studies throughout the 1990s further identified the critical role of NMDA receptors in eliciting stress-related behavioral deficits and in the generation of antidepressant-like effects in rodent models while postmortem studies in humans reported specific abnormalities in NMDA receptor function in the brains of depressed patients and suicide victims.7

    In 2000, Berman and colleagues were the first to demonstrate the rapid onset of antidepressant effects with an NMDA receptor antagonist.8 In a small, placebocontrolled, proof-of-concept, crossover study of 7 patients, they found that a subanesthetic dose of ketamine (0.5 mg/kg) administered via a 40-minute infusion elicited robust antidepressant effects within hours of administration that lasted for several days.

    However, it was a follow-up study of 17 treatment-resistant patients with MDD by Zarate and colleagues that truly ignited interest in the NMDA receptor as a viable target for antidepressant drug development.9 This placebo-controlled, randomized, crossover study found 71% of the participants to have a greater than 50% reduction in depressive symptoms within 24 hours of ketamine administration, while the same participants showed almost no change in symptoms following the placebo saline injection. Moreover, the response was sustained for the 1-week follow-up in approximately one-third of the participants. There have been 3 additional placebo-controlled crossover studies that showed very similar findings of rapid onset of robust antidepressant activity lasting for several days to weeks after a single subanesthetic dose of ketamine in the treatment of major depressive episodes associated with both MDD and bipolar disorder.10-12

    Numerous open-label studies and case series provide additional evidence of ketamine’s antidepressant effect and further characterize its effects in unique patient populations. Rapid reductions in suicidal ideation in depressed patients who received ketamine have been reported.13, 14 Other studies have begun to examine the potential benefits of adding ketamine to the anesthetic regimen of patients undergoing ECT. While some early reports suggest benefits, the proper use of the drug in this situation may need to be more clearly detemined.15, 16 Still other reports have begun to evaluate the potential use of ketamine in palliative care settings, where the drug’s pain-reducing effects may provide an additional benefit.17, 18

    Phelps and colleagues report that individuals with a family history of alcohol dependence had significantly greater mood improvement following ketamine infusion than those who had no family history of alcohol dependence.19 On the basis of these findings, a study (clinicaltrials.gov identifier: NCT01551329) is evaluating the efficacy of ketamine in reducing depressive symptoms in patients with a comorbid major depressive episode and alcohol dependence. In an attempt to examine the potential benefits of ketamine treatment outside of mood disorders, a recent study in patients with obsessive-compulsive disorder showed ketamine to have sustained effects on comorbid mood symptoms but only very transient effects on obsessions and compulsions.20 Another recently initiated study (NCT00749203) is attempting to investigate whether ketamine decreases symptoms of PTSD.

    Unresolved issues and concerns

    The aforementioned studies with ketamine have generated great interest from both academic centers and the pharmaceutical industry. However, there remain several unresolved issues with the studies and concerns about the drug’s safety in this setting that need to be better addressed before widespread implementation in clinical practice. First, there is the concern that none of the studies published to date have been able to maintain a true blind. Since the effects of ketamine on perception and cognition are usually evident to both the patient and the investigators, the blind is likely compromised in studies in which saline is used as the placebo control. Attempts are now under way to more effectively institute blinding by using midazolam as the comparator in a randomized clinical trial (NCT00768430).

    Second, the optimal dose and route of delivery have yet to be determined. Most studies use the 0.5 mg/kg dose delivered by IV infusion over 40 minutes, as initially reported in the Berman study over a decade ago. Studies are under way that examine both the optimal dose range (NCT01558063 and NCT01441505) and alternative routes of administration (NCT01304147).

    Third, and perhaps the most clinically important unknown, is whether it will be possible to maintain the ketamine-induced antidepressant response for a sustained period. A recent study found that a single sub-anesthetic dose of ketamine provides a moderate antidepressant effect over a 28-day follow-up period and that 27% of ketamine responders maintain improvement for 4 weeks following a single ketamine infusion, The average time to relapse was approximately 2 weeks, however.21 This result has prompted a search for novel ways of extending the antidepressant response. A few preliminary studies that attempted to extend the response with oral medication strategies have not yet shown success, but results of a study of 6 open-label ketamine infusions over 12 days suggest that the effect can be safely extended with a limited number of repeated doses.22 Other studies investigating the value of repeated ketamine dosing in sustaining the antidepressant response are now under way (NCT01582945 and NCT00548964).

    The use of repeated dosing underscores the potential safety concerns of ketamine. Ketamine has been used in hundreds of thousands of patients worldwide for surgical anesthesia and emergency medical procedures since 1965, and it is considered to have a “high degree of safety” when used for procedural sedation.23 However, there remain safety concerns surrounding the drug’s acute and chronic physiological and psychological effects, its abuse liability, its effects on the kidneys and liver, and also its potential neurotoxicity.

    NMDA receptor antagonists
    The adverse effects of long-term treatment need to be carefully considered when evaluating the risk to benefit ratio associated with ketamine. Would other NMDA antagonists provide a similar benefit without the same level of potential risks? Memantine, a relatively weak NMDA receptor antagonist did not show efficacy superior to that of placebo in several small proof-of-concept studies in MDD, bipolar disorder, and late-life depression.24-26 However, the full dose range of the drug had not been tested in the studies and final results from several ongoing studies have not been reported yet.

    A large, phase 2, multisite clinical trial (NCT00781742) of another nonselective NMDA antagonist—AZD6765—that enrolled 152 participants was recently completed. The results of this study that examined the safety and efficacy of 2 drug doses administered multiple times over a 3-week period and results of 2 smaller studies (NCT00491686 and NCT00986479) that examined the safety and efficacy of a single infusion of AZD6765 should be available soon. A second, larger, phase 2, repeated-dosing study (NCT01482221) with this drug is currently under way. Its aim is to recruit more than 280 participants internationally.

    Other studies have begun to investigate the effects of more selective NMDA receptor drugs. A positive study was reported with traxoprodil (CP-101,606), an NMDA receptor antagonist with relative selectivity for the NR2B-containing subset of NMDA receptors. The study of 30 patients who had not responded to a prospective, 6-week, open-label trial of paroxetine showed a 60% response rate at day 5 compared with a 20% response rate for placebo. The data suggest that the antidepressant effects are not limited to some unique properties of ketamine.27 However, not all doses used in this study were free of psychotomimetic effects. A small proof-of-concept study (NCT00472576) that examined the effects of orally administered MK-0657, another selective NR2B NMDA antagonist, was also recently completed and the results should be available shortly.

    Following on the exciting findings in fear extinction and phobia treatment, there are a number of studies on the effects of D-cycloserine—the same partial agonist at the NMDA receptor-glycine site reported on by Crane in the 1950s—in a variety of neuropsychiatric disorders, including depressive symptoms.28 A phase 2 study (NCT01234558) currently enrolling 80 participants to investigate the safety and efficacy of single-dose administration of a novel NMDA receptor glycinesite functional partial agonist, GLYX-13, should be completed in the near future.

    Glutamatergic neurotransmitter system
    In addition to studies specifically examining the potential antidepressant efficacy of drugs that target the NMDA receptor, there are several ongoing early-phase clinical trials evaluating the efficacy of drugs that target other components of the glutamatergic neurotransmitter system. (Figure 2 illustrates some of these pharmacological targets.)

    Interest in the novel glutamatergic drug riluzole, which appears to modulate both glutamate release and clearance and is currently FDA-approved for the treatment of amyotrophic lateral sclerosis, was fueled by evidence of its antidepressant-like and neuroprotective properties in humans and rodent models. Several small open-label studies have reported positive results in a variety of mood and anxiety disorders.29 The first large, multisite, placebo-controlled, randomized clinical trial in treatment-resistant MDD (NCT01204918) is under way and actively recruiting. A second, smaller, randomized clinical trial in bipolar depression (NCT00376220) has been completed recently, and results should be available shortly. Other studies that are evaluating riluzole’s effects in a variety of disorders as well as in the pediatric population are also currently under way.

    Based on preclinical evidence that demonstrates that mGluR5 antagonists possess antidepressant and anxiolytic effects, a phase 2 clinical trial (NCT00809562) with a novel mGluR5 antagonist, RO4917523, examined safety and efficacy in a population of patients with treatment-resistant MDD. The trial was recently completed, but the results are not yet available. Similarly, a study (NCT01457677) evaluating the antidepressant properties of an mGluR2/3 antagonist, RO4995819, was recently initiated on the basis of strong evidence that suggests that this class of drugs has potent antidepressant effects in rodent models. A second drug, BCI-838, that acts as an mGluR2/3 antagonist is currently in phase 1 studies (NCT01548703).

    Finally, there is growing interest in the effects of N-acetylcysteine (NAC) on glutamate neurotransmission and in NAC as treatment of a variety of neuropsychiatric disorders. In addition to its function as a glutathione precursor, NAC modulates glial glutamate release through its actions on the glutamate/cystine antiporter and can modulate extracellular levels in specific brain regions. Preliminary studies suggest that NAC may be an effective augmentation strategy for the treatment of bipolar depression, but follow-up studies are needed.30

    There is rapidly escalating interest in drugs that target the glutamatergic neurotransmitter system, especially NMDA receptor modulators. The hope is that they will fill the large unmet need for rapid-acting antidepressant medications with efficacy in treatment-resistant patients.31 While early-phase clinical studies provide strong evidence that this novel class of drugs may advance our ability to treat mood disorders, the treatments remain in the realm of experimental therapeutics. Several important questions still need to be answered related to dosage, efficacy compared with a truly blinded placebo, and duration of effect of these drugs.

    There are several known potential risks associated with ketamine administration, including physiological and psychological effects, substance abuse liability, cystitis, and hepatotoxicity, that should be seriously considered before initiating a trial of ketamine for the treatment of a mood disorder. At the present time, consideration of ketamine or similar drugs should be limited to patients with well-documented treatment-resistant depressive episodes.

    Whenever possible, it is prudent to consider enrolling a patient in one of the multiple ongoing clinical trials that are available in many locations around the country. Scrutiny of the study protocols by institutional review boards before trial initiation helps ensure patient safety in these clinical trials. In addition, it is important to remember that patient participation in these well-controlled and well-documented clinical trials is required to ultimately provide answers to the many questions regarding the ultimate safety and efficacy of this novel class of medications.

    Clinicaltrials.gov is a valuable resource to guide clinicians and patients to local clinical trials or studies allowing for longer-term inpatient stays, and should serve as a primary reference for clinicians considering these novel treatments for patients.

    Psychiatric Times. Vol. 29 No. 7


    1 National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study.http://www.nimh.nih.gov/trials/practical/stard/index.shtml. Accessed April 27, 2012.
    2 National Institute of Mental Health. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). http://www.nimh.nih.gov/trials/practical/step-bd/index.shtml. Accessed April 27, 2012.
    3 Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem. 1984;42:1-11.
    4 Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13:22-37.
    5 Crane GE. Cycloserine as an antidepressant agent. Am J Psychiatry. 1959;115:1025-1026.
    6 Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185:1-10.
    7 Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:25-272.
    8 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
    9 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.
    10 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.
    11 Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191:122-127.
    12 Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939-946.
    13 DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-d-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605-1611.
    14 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.
    15 Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A. Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: a retrospective study. Eur Arch Psychiatry Clin Neurosci. 2011;261:575-582.
    16 Abdalla CG, Fasula M, Kelmendi B, et al. The rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. J ECT. In press.
    17 Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 2010;13:903-908.
    18 Kerr C, Holahan T, Milch R. The use of ketamine in severe cases of refractory pain syndromes in the palliative care setting: a case series. J Palliat Med. 2011;14:1074-1077.
    19 Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009;65:181-184.
    20 Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. In press.
    21 Ibrahim L, Diazgranados N, Frnaco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double blind, placebo-controlled study. Neuropsychopharmacology. 2012;37:1526-1533.
    22 aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139-145.
    23 Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults [published correction appears in Am J Emerg Med. 2009;27:512]. Am J Emerg Med. 2008;26:985-1028.
    24. Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163:153-155.
    25 Anand A, Gunn AD, Barkay G, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2012;14:64-70.
    26 Lenze EJ, Skidmore ER, Begley AE, et al. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry. 2011 Dec 16; [Epub ahead of print].
    27 Preskorn SH, Baker B, Kolluri S, et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refratory major depressive disorder. J Clin Psychopharmacol. 2008;28:631-637.
    28 Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry. 2006;60:369-375.
    29 Pittenger C, Coric C, Banasr M, et al. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22:761-786.
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  3. Calliope
    Ketamine, Cum Grano Salis

    [IMGL="white"]http://www.drugs-forum.com/forum/attachment.php?attachmentid=31119&stc=1&d=1358924172[/IMGL]The findings reported in Arline Kaplan’s article on ketamine (New Claims and Findings for Ketamine in Severe Depression ), are certainly exciting, particularly for those of us who have attended the considerable suffering of many patients with treatment-resistant depression (TRD). TRD has been defined in various ways, but recent opinion has considered TRD as depression that has responded inadequately to at least 2 trials with antidepressants from different pharmacological classes, with adequate dosage, duration, and adherence to treatment.1 TRD may occur in as many as 60% of depressed patients,2 and effective remedies are hard to come by. If the early and encouraging ketamine findings are borne out in large, randomized, double-blind, controlled studies, this will represent a significant advance in our treatment options for MDD.3

    And yet, there are several reasons for taking the ketamine findings with a substantial grain of salt. First, there is history. Those of us who have been treating mood disorders for the past 30 or more years have seen many “amazing new remedies” fizzle out, once tested in carefully controlled trials. This is not to diminish the importance or integrity of the ketamine research thus far. It is only to say that the number of ketamine-treated patients is still small; the duration of study, quite short; and the durability of ketamine’s apparent benefits, limited to a few weeks. Notably, to my knowledge, there have been no controlled studies comparing ketamine (via infusion or other modality) with an active control (ie, a drug that produces some alteration in consciousness beyond the placebo effect of saline). It is encouraging, however, that such an active-control study is under way at New York State Psychiatric Institute, in which depressed participants are randomly assigned to receive a single intravenous dose of either ketamine or midazolam (a short-acting benzodiazepine with pronounced amnestic effects).4

    I also wonder whether the informed consent process for ketamine treatment has included a discussion of alternative treatments known to be effective for TRD; for example, electroconvulsive therapy (ECT). Yes, I’m well aware that ECT carries its own risks (including cognitive side effects) and that there are many administrative and psychological barriers to its availability. Nevertheless, ECT is “acknowledged as the most effective acute treatment for severe mood and psychotic disorders.”5 Surely, a patient with severe, treatment-resistant MDD should be apprised of ECT as an alternative to a ketamine trial, if consent is to be fully “informed.” And, in my view, other agents with well-documented efficacy in TRD—such as adjunctive lithium or triiodothyronine (T3)6—should also be included in the informed consent process, assuming the patient has not already tried these agents.

    Finally—though this may surprise some who consider “treatment” in psychiatry to include only somatic therapies—there are also good rea-sons to consider psychotherapy in some nonmelancholic, nonpsychotic cases of TRD.7-9 Although studies are quite limited and methodologically flawed, one recent review concluded that “primary care providers should consider psychotherapy when treating patients with treatment-resistant depression.”8

    All that said, I well understand that some TRD patients are acutely suicidal and may not benefit quickly from “established” treatments that require weeks or months for full effect. In such cases, and after a thorough informed consent process (which is more than signing a “form”), a ketamine trial may indeed be worth considering.

    Psychiatric Times
    By Ronald Pies, MD | January 17, 2013


    1 Berlim MT, Turecki G. "Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods." Canadian Journal of Psychiatry. 2007;52:46-54.
    2 Fava M. "Diagnosis and definition of treatment-resistant depression." Biological Psychiatry. 2003;53:649-659.
    3 Pies R. "Are antidepressants effective in the acute and long-term treatment of depression?" Sic et non. Innov Clin Neurosci. 2012;9:31-40.
    4 Kellner CH, Greenberg RM, Murrough JW, et al. "ECT in treatment-resistant depression." Am J Psychiatry. 2012;169:1238-1244.
    5 McIntyre RS, Müller A, Mancini DA, Silver ES. "What to do if an initial antidepressant fails?" Canadian Fam Physician. 2003;49:449-457.
    6Brown WA."Treatment response in melancholia." Acta Psychiatr Scand Suppl. 2007;(433):125-129.
    7Trivedi RB, Nieuwsma JA, Williams JW Jr. "Examination of the utility of psychotherapy for patients with treatment resistant depression: a systematic review." J Gen Intern Med. 2011;26:643-650.
    8 Wiles N, Thomas L, Abel A, et al. "Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial." Lancet. 2012 Dec 6; [Epub ahead of print]. doi:10.1016/S0140-6736(12)61552-9.
  4. quickiB
    What are you talking about? Are you saying that these kinds of trials should not be attempted?
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