On May 19, James Murrough, MD, PhD, director of Mount Sinai’s Depression and Anxiety Center for Discovery and Treatment, and Martijn Figee, MD, director of Mount Sinai’s Interventional Psychiatry Program, chaired a session on next-generation solutions for treatment resistant depression (TRD). The speakers covered ketamine, inflammation, deep brain stimulation (DBS), and electroconvulsive therapy (ECT).
Ketamine: Then, now, and looking ahead
Dr. Murrough discussed how the road to discovering new treatments for TRD has been paved with medications that have almost identical biological mechanisms, and that a new pathway—like targeting the glutamate system via ketamine—has been an inevitable next step. The first iteration of this, Janssen’s newly approved SPRAVATO (esketamine) CIII Nasal spray, could bring relief to millions of patients. Dr. Murrough discussed the first multi-site clinical trial of ketamine in TRD, studies on repeated dosing of ketamine for TRD, and the first study of intranasal ketamine in TRD—all conducted at Mount Sinai. He also covered the rapid antidepressant effects of the novel GABA-A modulator brexanolone, which the FDA recently approved for the treatment of postpartum depression. He concluded that the long-term efficacy and effects of ketamine remain to be seen, but based on preliminary rodent studies he believes the treatments will need to be regular and conducted indefinitely in order to maintain efficacy in patients.
Dr. Murrough discussing ketamine at the APA Annual meeting in San Francisco.
A subgroup: Patients with inflammation
Andrew Miller, MD, professor of psychiatry and behavioral sciences at Emory University, showed that as many as 25-30 percent of depressed patients exhibit the primary features of chronic inflammation. He covered how administration of inflammatory stimuli causes depressive symptoms, and how inhibition of inflammation reduces depressive symptoms. In addition to targeting the inflammation directly, he recommends targeting the “downstream effects” of inflammation on the brain, such as dopamine and glutamate systems. Dopaminergic medications these patients may respond to include bupropion, stimulants, monoamine oxidase inhibitors, and dopamine agonists. This targeted treatment, available by way of the red flag of inflammation, means precision medicine is possible for these patients.
Deep brain stimulation
Dr. Figee brought the backstory on DBS, a treatment that uses implanted electrical impulses to control symptoms for a range of psychiatric and neurologic diseases. In patients with TRD, DBS targets are part of a larger ventral corticostriatal network involved in the regulation of negative and positive mood. Although DBS is effective in approximately 50 percent of patients with TRD, it is still experimental and can only be received as part of a clinical trial. Before taking this step, however, Dr. Figee emphasizes that patients need to have gone through a variety of attempts at treatment including psychotherapy, a variety of antidepressants, at least six sessions of ECT, and possibly repetitive transcranial magnetic stimulation and ketamine. In order to be considered for DBS, the patient must have suffered from TRD for less than two years, and exhibit no schizophrenia/non-affective psychosis, no primary Axis II personality disorder, and no cerebrovascular risk factors. They must also have no other implanted devices, no drug abuse in the past six months, and no cognitive impairment or mental retardation. For more information, check out the Nash Family Center for Advanced Circuit Therapeutics.
A slide from Dr. Figee’s talk on deep brain stimulation.
Ketamine and ECT for apathy, anhedonia, and suicidal ideation
Katherine Narr, PhD, professor of neurology, psychiatry, and biobehavioral sciences at The University of California, Los Angeles, discussed how ECT and ketamine are highly effective at reducing symptoms of apathy, anhedonia (reduced ability to feel pleasure), and suicidal ideation in patients with TRD. ECT has its advantages in that about 70 percent respond and about 50 percent achieve remission, and it’s fast-acting (within 2-4 weeks), it has no systemic effects (unlike medications). Its disadvantages, on the other hand, include stigma, anesthetic effects, cost, cognitive side effects, and the fact that approximately 50 percent relapse within six months. As for ketamine, the pros include that 50-70 percent respond positively, it’s fast-acting (within hours), and has been used safely as an anesthetic since the 1960s. The disadvantages, however, are durability (approximately one week), potential psychotic and dissociative effects, it’s an easy drug to abuse, and the high cost. She concluded that over the short term, ketamine may be as effective as clinically prescribed ECT for reducing depression, apathy, anhedonia, and suicidal ideation.