By Margaret Wehrenberg


But what do we do while we wait?

I don’t typically write about medications because I do not prescribe them. I am a psychologist and treat people with psychotherapy methods. Research consistently shows that psychotherapy is incredibly helpful to people with depression, but it is not all that people may need when they suffer severe and chronic depression. Then medication is necessary. Current medication options are not sufficient for all the types of depression people experience, and it is with interest that I have followed news about the potential of ketamine since a study in 2008 suggested it as promising for rapid reduction of severe depression.

This is a compelling issue because ketamine is an animal anesthetic, abused by some people as a club drug, referred to as Special K or K (and many other names). It has dangerous side effects. When ingested it causes hallucinations, dissociative experiences, distorted perceptions and in excess it can be lethal. Yet it has garnered interest in the mental health community for a surprising impact on severe, suicidal depression episodes. In the last several years, a few studies have shown a rapid relief of suicidal depression that lasted briefly — a week or so — before the relief faded. It is exciting to think there is a drug with such rapid and effective relief from refractory (hard-to-treat) depression. But no one has known why it has that effect, speculating it has something to do with blocking glutamate (NMDA) receptors. Glutamate is an excitatory neurotransmitter.

But holding promise does not mean it is the next right thing to use. In fact, I recently read in Medscape Medical News (April 25, 2016) Charles Nemeroff’s, M.D., PhD., wise comments on the troubling trend of physicians prescribing ketamine ‘off-label’ for relief of severe or suicidal depression. (Off-label use means that physicians prescribe it for uses other than it was approved for.) People are impatient for answers to the epidemic of depression and, reasonably, want answers to help with this devastating condition. But using it off label means making a guess about dose and hoping for a good outcome while not knowing much about it, either why it works or about potential damaging side-effects — not really a good plan for safe use of a medication.

Until two weeks ago, there was promise without clear knowledge about why it helped, but on May 4, 2016, a press release from the National Institute of Mental Health reported that a team of scientists, working on related studies, found the anti-depressant action of ketamine occurs not from ketamine, but from the action of a metabolite of ketamine, hydroxynorketamine, created as the body breaks down ketamine. It activates the AMPA receptor, a different receptor than the NMDA glutamate receptor that ketamine blockades. That metabolite can reverse depression without triggering any of the negative side effects of ketamine. The combined efforts of the team or researchers made this discovery, and involved researchers Carlos Zarate, Todd Gould, Irving Wainer, Ruin Moaddel.


The action now is much better understood, but we are still a long way from having a drug safe for human use. The good news/bad news scenario for anyone with severe depression that has not responded to treatment is that researchers believe they have a new drug to develop for fast relief of depression. The bad news is how long it takes to get it to market safely. That’s where the National Center for Advancing Translational Sciences (NCATS) comes in. Their website states “NCATS is all about getting more treatments to more patients more quickly. Several thousand genetic diseases affect humans, of which only about 500 have any treatment. A novel drug, device or other intervention can take about 14 years and $2 billion to develop, with a failure rate exceeding 95 percent. NCATS is directly addressing this problem by discovering new technologies and other approaches that could greatly accelerate the process of developing and deploying solutions that can be used by all translational researchers. […] NCATS studies translation on a system-wide level as a scientific and operational problem.” Using government research funds to move projects along when they hold as much promise as this one makes sense, and the research outcomes of this team, working separately but in concert, reflects how well this can work.

In the meantime, we in the mental health field working with people who suffer depression are not without options. Many people with significant depression do respond to the selective serotonin reuptake inhibitors (SSRIs) and other medications can be used to augment the impact of those medications. But I want to put in a word for encouraging clients who suffer to carry out the self-care that genuinely holds promise for relief, if not full remission of depression. So as a reminder, and even if you are holding steady, waiting for the next beneficial medication, check out these options:

  • David Burns new T.E.A.M. method for rapid relief of depression. He is very optimistic about this method and is currently training therapists to use this approach.
  • Mindfulness: the research fully supports mindfulness as a way to immediately loosen the grip of neurobiologically based cognitive over-focus on negative aspects of a situation that seems to be a hallmark of depressive cognition. Learning mindfulness is easy, safe and has no negative side effects.
  • Exercise: almost daily, there is more science about the profound mental benefits of vigorous physical exercise. For example, recent studies indicate it is one of the most effective means of increasing galanin and neuropeptide Y, two peptides that are protective against the neurobiological impact of stress and its consequent depression. Also, subsequent to exercise, the brain’s ability to increase production of serotonin is improved, as is the attitude of the person who exercised. People with depression are unlikely to want to exercise this way, but knowing the possibilities for improvement may make a difference, moving them in the direction of trying. This is the perfect scenario for a trainer or a friend to encourage a depressed person to move more often and more energetically.
  • Eat right: You are what you eat. So make sure you are getting nutrients, not just calories. But even more, research about gut microbes and their connection to producing enough serotonin (a neurochemical involved in mood regulation) is pouring in. It is possible that the use of probiotics helps depression, especially if there is a reason to believe the gut is not full of healthy microbes due to digestive disorders, significant stress, or extensive use of antibiotics. While this is still new science, taking a probiotic is not a treatment with great potential for harm.
  • Sleep: U.S. Citizens are typically under-sleeping and there is no question that sleep is restorative at every level, including brain-mind health.

While science searches for medications that can turn around serious and refractory depression, there are things any of us can do that will promote brain health. Remember that one feature of depression is lethargy of mind and will, so any person suffering this disorder may need help fm those family and friends who can encourage them in the daily habits that might create the best brain health possible without medication.