Dr. J. John Mann

For much of his career, J. John Mann, MD, has sought to understand the molecular mechanisms of antidepressants in order to design medications that work better and faster for patients. “All FDA- approved antidepressants still take weeks to work, and it is very difficult to predict which anti-depressant is going to help a patient,” says Dr. Mann, the Paul Janssen Professor of Translational Neuroscience in the Departments of Psychiatry and Radiology at Columbia University Irving Medical Center and Director of Molecular Imaging and the Neuropathology Division at the New York State Psychiatric Institute. “This trial-and-error approach to treatment selection leaves the patient sometimes feeling depressed for many weeks until we find the right dose of the right antidepressant or combination of antidepressants. Given how painful and disabling depression is as an illness, this is a big problem.”

Some 15 million Americans suffer from an episode of depression every year, and by 2030, it is estimated that depressive illness will account for more disability than any other illness worldwide – more than cancer, cardiovascular disease, malnutrition, and infectious diseases. In addition, mood disorders are the most common cause of suicide, which is the second leading cause of death in people between the ages of 15 and 25 and accounts for about 45,000 deaths per year in the United States.

“Figuring out a way to treat depression more reliably and with a quicker response is one of the major medical priorities for the United States and the world,” says Dr. Mann, whose research employs functional brain imaging, neurochemistry, and molecular genetics to probe the causes of depression and suicide.

To that end, Dr. Mann and his Columbia colleagues have been investigating the use of ketamine as a treatment option for rapidly reducing suicidal thoughts in patients with refractory depression. “Ketamine offers a new possibility for treatment because it has been shown in a number of clinical trials – including two large NIH-funded clinical trials conducted here at Columbia – to be an effective antidepressant that produces a generally robust antidepressant effect within hours,” says Dr. Mann.

Ketamine is also known as a party drug due to its hallucinogenic and tranquilizing effects. “It does produce a sense of derealization and some sensory distortions, but it’s transient, when administered intravenously over 40 minutes under medical supervision,” says Dr. Mann.

In their first NIH trial, the Columbia researchers tested ketamine in depressed patients only; their second trial included depressed patients with a history of a suicide attempt or suicidal ideation. According to the researchers, ketamine not only works as an antidepressant, but it also has a profound anti-suicidal effect. “That’s very valuable in patients who are feeling suicidal. Not only do they potentially get better, but the suicidal thoughts can fade dramatically,” says Dr. Mann. “In an occasional subgroup of people treated with regular anti-depressants, the depression sometimes begins to improve, and they become energized before the suicidal thoughts go away. Under those circumstances, the risk of suicide increases, paradoxically. That doesn’t happen with ketamine because it has a fast effect on both the depression and the suicidal impulse.”

Medial prefrontal cortical levels of glutamate + glutamine (Glx) and y-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy.

The full benefit of ketamine lasts for about five to seven days and partial benefit can last for weeks, says Dr. Mann. “We’ve given it to people while they’re taking antidepressants and then we’ve adjusted their antidepressants to what we regard as optimal. We find that the benefits under those circumstances are fully maintained for many weeks.”

In a pilot study, Columbia researchers examined the relationship between antidepressant effect and ketamine dose. Eleven depressed patients were given ketamine during proton magnetic resonance spectroscopy. “We knew from animal studies that ketamine produces an increase in the amount of glutamate, the primary excitatory, or activating, neurotransmitter in the brain,” explains Dr. Mann. “At the same time, ketamine blocks one of the glutamate receptors, NMDA, that mediates the excitatory or potentially neurotoxic action of glutamate. However, it does not block the AMPA receptor, which mediates a brain-trophic effect of glutamate. The increase in these synapses in mice happens within hours. At the end of the hour-and-a-half scan period, the patients were feeling much better. So, we think the two are related.”

In a second double-blind control trial, the results of which were published in the American Journal of Psychiatry in April 2018, 80 depressed adults with clinically significant suicidal thoughts were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, those in the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

“Figuring out a way to treat depression more reliably and with a quicker response is one of the major medical priorities for the United States and the world.”

— Dr. J. John Mann

Those in the ketamine group also had greater improvement in their overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, which suggests that the treatment has a specific anti-suicidal effect. “The side effects during the infusion, mainly dissociation, were mild to moderate, typically resolving within minutes to hours,” says Dr. Mann.

The number of ketamine infusions varies from patient to patient. “We’ve been using ketamine in either one dose and then putting the patient on regular antidepressants, or sometimes others have used repeated doses,” says Dr. Mann. “A patient might get two doses a week for three weeks, and then one dose a week for a few more weeks, and then one dose a month. Eventually, one tries to manage the depression without using the ketamine at all.”

“As a researcher and clinician who has been treating depression for over 30 years, I’ve seen the painful consequences of untreated depression,” adds Dr. Mann. “Studies like these may help us give more hope to those who are suffering.”