By Bob Murray

New method helps identify causal mechanisms in depression

A new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging looks at the driving influence of brain regions in depression.

What the researchers say

The researchers note that people with major depressive disorder have alterations in the activity and connectivity of brain systems underlying reward and memory. The findings provide clues as to which regions of the brain could be at the root of depressive symptoms, such as reduced happiness and pleasure.

The research uses a new approach to measure the influence of one brain region on another, referred to as effective connectivity, in depression. The approach goes beyond the limitations of previous brain imaging studies, which show if—but not how—activity of different brain regions is related. “The new method allows the effect of one brain region on another to be measured in depression, in order to discover more about which brain systems make causal contributions to depression,” said the lead researcher.

“This represents an exciting new methodological advance in the development of diagnostic biomarkers and the identification of critical brain circuitry for targeted interventions for major depression,” he added.

The team compared 336 people with major depressive disorder to 350 healthy controls. Brain regions involved in reward and subjective pleasure received less drive (or reduced effective connectivity) in depressed patients, which may contribute to the decreased feeling of happiness in depression.

In addition, brain regions involved in punishment and responses when a reward is not received had decreased effective connectivity and increased activity, providing evidence for the source of sadness that occurs in the disorder.

Memory-related areas of the brain had increased activity and connectivity in people with depression, which the authors suggest may be related to heightened memory processing, possibly of unpleasant memories, in depression.

“These findings are part of a concerted approach to better understand the brain mechanisms related to depression, and thereby to lead to new ways of understanding and treating depression,” said the researchers.

So, what?

This study, together with the first one reported here, show that there is an increasing interest in the connectivity of the brain in the development of depression—or at least some depression since there are potentially many, many, forms of the disease. Certainly, the idea of looking at the connectivity that underlies the experience—or lack of experience—of pleasure or the inability to remember pleasurable things or experiences is novel. If depression really is a collection of diverse symptoms with some zillion possible origins, then it makes perfect sense to target the symptomology since the underlying cause—biological or experiential—may be impossible to identify or treat in any individual.

Does ketamine really work as an antidepressant?

Antidepressant response within hours, or a blind alley? Experts weigh evidence on ketamine as a fast-acting treatment for depression in an article in the Harvard Review of Psychiatry.

Recent studies suggest that ketamine, a widely used anesthetic agent, could offer a wholly new approach to treating severe depression—producing an antidepressant response in hours rather than weeks. Two reviews of recent evidence on ketamine and related drugs for treating depression appear in the journal.

In one paper the researchers at the US National Institute of Mental Health claim that ketamine and related drugs may represent a “paradigm shift” in the treatment of major depressive disorder (MDD) and bipolar depression—especially in patients who do not respond to other treatments.

A second article explores the evidence on the mechanisms behind ketamine’s rapid antidepressant effects.

Current treatments for MDD and bipolar depression have major limitations. Most patients with severe depressive symptoms don’t respond to available antidepressant drugs. Even for those who do respond, it may take several weeks before symptoms improve.

Ketamine is one of several glutamatergic drugs (i.e. those that target the glutamate system) affecting neurotransmitters in the central nervous system. Over the past decade, several studies have reported “rapid, robust, and relatively sustained antidepressant response” to ketamine, injected intravenously at low, subanesthetic doses.

Ketamine may also rapidly reduce suicidal thoughts and has become a first-line treatment for suicidality in many countries. Combined with other medications, ketamine has also produced rapid antidepressant effects in patients with treatment-resistant bipolar depression.

Prompted by these studies, some doctors are already using ketamine in patients with severe or treatment-resistant depression. However, since it is FDA-approved only as an anesthetic, use of ketamine in depressive disorders is “off-label,” unregulated, and not standardized. Many questions remain about its short- and long-term side effects and potential for abuse (in a refined form it is a street drug called “special K”).

“Efforts are underway to bring ketamine to market, standardize its use, and determine its real-world effectiveness,” the NIH coauthors write. They also present evidence on several other glutamatergic drugs. One drug, ketamine, has been given “breakthrough therapy” status by the FDA for patients at imminent risk of suicide.

Researchers from the Massachusetts General Hospital reviewed neuroimaging studies evaluating ketamine’s effects in the brain. The studies show ketamine-induced changes in several brain areas involved in the development of depression. Ketamine may exert its antidepressant effects by “acutely disabling the emotional resources required to perpetuate the symptoms of depression,” as well as by increasing emotional blunting and increasing activity in reward processing.

Independent of how ketamine works or its ultimate role in clinical treatment, antidepressant response to glutamatergic drugs points to an exciting conclusion: “that rapid antidepressant effects are indeed achievable in humans,” they write. “This paradigm shift lends additional urgency to the development of novel treatments for MDD and bipolar depression, particularly for patient subgroups that do not respond to currently available therapies.”

So, what?

At the present time we know that ketamine and similar drugs are an excellent immediate therapy for suicidal patients or those whose MDD is too severe for them to operate in the world. We know nothing of its medium-to-long term effects, but it is an exciting area for further study. What we do know is that, at least in the very short term, it works for everyone with severe depression. That’s the very good news.

To sum up

The science of depression and related disorders is quickening, and that, at least in the long term, is very good news for individuals and for society as a whole. However, business has a very big role to play. We need to urgently reduce the level of workplace stress which will have increased by over 200% between 2010 and 2020. This is totally unsustainable. Business leaders, HR professionals and the like must insist that the research is taken note of and that appropriate changes are made.

It doesn’t take much to reduce the level of stress, and therefore depression, and it’s not really that expensive. The rewards in productivity gains and engagement are huge. It only takes the will. That’s the ultimate truth about depression.

About Dr. Bob Murray

Bob is the author (with Dr. Alicia Fortinberry) of best sellers “Creating Optimism” and “Raising an Optimistic Child” (both Mc Graw-Hill). He has lectured at Duke, Tufts, Sydney and California State Universities as well as working with University of South Florida on the anti-depression “Uplift Program.” He is a consultant with the firm of Fortinberry Murray and is on the Advisory Board of the Mental Health Institute of Legal Professions. His most recent book is “Leading the Future: The human science of law firm strategy and leadership.” He can be reached at