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Current Status of Ketamine and Related Therapies for Mood and Anxiety Disorders

Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Despite a plethora of established treatments, less than one-third of individuals with MDD achieve stable remission of symptoms. Given limited efficacy and significant lag time to onset of therapeutic action among conventional antidepressants, interest has shifted to treatments that act outside of the monoamine neurotransmitter systems (e.g., serotonin, norepinephrine, and dopamine).

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Is ketamine the best hope for curing major depression?

On the seventh floor of a building overlooking the Federal Reserve Bank in lower Manhattan, two medical clinics share an office. One is run by a podiatrist who’s outfitted the waiting room with educational materials on foot problems such as hammer toes and bunions. The other clinic doesn’t have pamphlets on display and offers a much less conventional service: For the advertised price of $525, severely depressed and suicidal patients can get a 45-minute intravenous infusion of ketamine—better known as the illicit party drug Special K.

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The secret life of ketamine

It rains for 164 days out of each year in Portland, Oregon, a city renowned for its wet weather. So it seems an unlikely destination for patients hoping to alleviate their depression. Yet, over the past two years, almost a hundred people have visited a small nondescript clinic in this damp corner of Northwestern United States to receive ketamine, an experimental treatment for depression that can work where other drugs have failed.

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How does ketamine elicit a rapid antidepressant response?

A single sub-psychotomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist, produces a fast-acting antidepressant response in patients suffering from major depressive disorder. Depressed patients report alleviation of core symptoms within two hours of a single low-dose intravenous infusion of ketamine with effects lasting up to two weeks. The rapidity of ketamine action implies that major symptoms of depression can be alleviated without substantial structural plasticity or circuit rewiring. Therefore, the ability of ketamine to exert a rapid effect provides a unique opportunity to elucidate the types of acute synaptic plasticity changes that can be recruited to counter depression symptoms.

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Ketamine: The Future of Depression Treatment?

Every year, 13 million to 14 million Americans have major depression. Of those who seek treatment, 30% to 40% will not get better or fully recover with standard antidepressants.

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Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients.

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Old Drug, New Tricks

Ketamine, better known as the club drug “Special K,” may alleviate depression when all other treatments have failed—a finding researchers stumbled across by accident.

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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.

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