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According to the National Institute of Mental Health, major depressive disorder (MDD) affects more than 16 million American adults in a given year. It is the leading cause of disability among individuals ages 15 to 44, and it can bring potential complications including substance abuse, cardiovascular disease, and suicide.

Although numerous medications are available for MDD, up to a third of patients are considered treatment-resistant after trying at least two approved therapies for at least eight weeks without experiencing improvement.

“This is a very significant problem, in terms of both the functional abilities of affected individuals and the burden it places on the people around them,” observes Dan Iosifescu, MD, MMSc, associate professor of psychiatry and director of clinical research at the ��ɫtv Langone Health–affiliated .

Dr. Iosifescu, who joined the ��ɫtv Langone faculty in March 2017, is leading groundbreaking research on novel MDD therapies, some of which bear little resemblance to previous generations of antidepressants.

The best known of these novel therapies may be ketamine, a common anesthetic that is also used as an illicit street drug. Over the past five years, a growing body of research has demonstrated that low doses of ketamine, administered via intravenous or intranasal infusion, can alleviate symptoms in many patients with treatment-resistant MDD. Although its precise mechanism of action remains unclear, ketamine is known to partially block N-methyl-D-aspartate receptors, which bind to the neurotransmitter glutamate.

“Ketamine works much faster than conventional antidepressants—within hours, rather than weeks,” Dr. Iosifescu notes. “That can be lifesaving for a patient with suicidal impulses.”

As evidence of the effectiveness of ketamine mounts, clinicians are increasingly administering it off-label to patients with resistant MDD. Nonetheless, Dr. Iosifescu cautions that the drug is not a panacea. One major caveat is that its effects tend to be short-lived, tapering off after a few days.

Another is that heavy use of ketamine has been associated with a form of brain damage known as Olney’s lesions in lab animals—and, in one 2013 study, in humans. The long-term side effects of multiple repeats of current therapeutic doses are unknown.

Atypical Antipsychotic May Prolong The Benefits Of Ketamine

Dr. Iosifescu is researching treatments that can prolong ketamine’s beneficial effects, allowing for less-frequent use. One promising candidate is brexpiprazole, an atypical antipsychotic, which has already been approved by the Food and Drug Administration (FDA) as an adjunctive treatment with standard antidepressants.

At the Nathan S. Kline Institute, Dr. Iosifescu is leading trials of brexpiprazole in combination with intranasal ketamine, as part of a five-site study in subjects with treatment-resistant MDD.

“Over the past five years, a growing body of research has demonstrated that low doses of ketamine, administered via intravenous or intranasal infusion, can alleviate symptoms in many patients with treatment-resistant MDD.” —Dan Iosifescu, MD, MMSc, director of clinical research at the Nathan S. Kline Institute for Psychiatric Research

Also under investigation are neuromodulation treatments, which employ various forms of electromagnetic energy to elicit changes in brain circuit activity. A familiar example is electro-convulsive therapy (ECT), used for decades on patients with MDD and other serious mental disorders. Because ECT works by inducing a seizure and carries a risk of adverse cognitive effects, it is used only after multiple other treatments have been unsuccessful.

In transcranial magnetic stimulation (TMS), a newer and gentler form of neuromodulation, a magnetic coil placed on the patient’s scalp near the forehead stimulates small regions of the brain—for MDD, the region is the dorsolateral prefrontal cortex.

Although repetitive TMS for treatment-resistant MDD was approved by the FDA in 2008, its efficacy has not been compared with that of other antidepressants. At ��ɫtv Langone, Dr. Iosifescu is leading a randomized, open-label effectiveness study, part of a multisite project funded by the Patient-Centered Outcomes Research Institute, testing TMS against two pharmacological treatments: the atypical antipsychotic aripiprazole as an add-on therapy to standard antidepressants and the serotonin-norepinephrine reuptake inhibitor venlafaxine as monotherapy.

Battling Depression With Lasers

Transcranial photobiomodulation, another form of neuromodulation, uses low-energy lasers to transmit near- infrared light through the skull into the brain. An emerging technique used to promote healing in various parts of the body, photobiomodulation is believed to work by stimulating activity in mitochondria, boosting cellular energy production.

In collaboration with researchers led by Paolo Cassano, MD, PhD, a psychiatrist at Massachusetts General Hospital, Dr. Iosifescu’s Nathan S. Kline Institute team is testing the therapy’s efficacy for treatment-resistant MDD in a randomized, double- blind study of approximately 50 subjects.

“For a large number of patients, the standard treatments for MDD are ineffective,” says Dr. Iosifescu. “By rigorously investigating new techniques and enhancing established ones, we hope to provide a new slate of options for these patients.”