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.
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.”
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 firstname.lastname@example.org
Dr. Bob Murray
Depression literally changes the brain over time
Importantly the new research found that persistent depression may need a different therapeutic approach from all those that have been tried so far. They findings also raised the question: Is clinical depression always the same illness, or does it change over time?
What the researchers say
New brain imaging research shows that the brain alters after years of persistent depression, suggesting the need to change how we think about depression as it progresses. The study was published in The Lancet Psychiatry.
The research shows that people with longer periods of untreated depression, lasting more than a decade, had significantly more brain inflammation compared to those who had less than 10 years of untreated depression. In an earlier study the team discovered the first definitive evidence of inflammation in the brain in clinical depression.
This study provides the first biological evidence for large brain changes in long-lasting depression, suggesting that it is a different stage of illness that needs different therapeutics—the same perspective taken for early and later stages of Alzheimer’s disease, the lead author says.
“Greater inflammation in the brain is a common response with degenerative brain diseases as they progress, such as with Alzheimer’s disease and Parkinson´s disease,” he adds. While depression is not considered a degenerative brain disease, the change in inflammation shows that, for those in whom depression persists, it may be progressive and not a static condition.
Yet currently, regardless of how long a person has been ill, major depressive disorder is mainly treated with the same approach. Some people may have a couple of episodes of depression over a few years. Others may have persistent episodes over a decade with worsening symptoms, including increasing difficulty going to work or carrying out routine activities.
Treatment options for this later stage of illness, such as medications targeting inflammation, are now being investigated. This includes re-purposing current medications designed for inflammation in other illnesses to be used in major depressive disorder
In the study, brain inflammation was measured using a type of brain imaging called positron emission tomography (PET). The brain’s immune cells, known as microglia, are involved in the brain’s normal inflammatory response to trauma or injury, but too much inflammation is associated with degenerative illnesses as well as depression.
The study involved 25 people with more than 10 years of depression, 25 with less than 10 years of illness, and 30 people with no depression as a comparison group. Inflammation levels were about 30 per cent higher in different brain regions among those with long-lasting untreated depression, compared to those with shorter periods of untreated depression. The group with long-term depression also had higher inflammation levels than those with no depression.
The researchers also note that in treatment studies, patients with serious, longstanding depression tend to be excluded, so there is a lack of evidence of how to treat this stage of illness, which needs to be addressed.
Treating depression with anti-inflammatory drugs is not a new idea. Nor is the idea that depression can increase in severity with age. What is new in this study is the idea that the two are linked and that depression becomes something very different involving changes in the way the brain functions over time. This will hopefully lead to the discovery of new and better treatments for people with long-standing depression—which is actually most depression sufferers of major depressive disorder over the age of 40.
A pathway to a better way to treat depression?
As I said at the start about 30-40% of depression is genetic in origin. A really interesting study just published, outlines a new and rather dramatic look at this aspect of depression. Essentially it indicates that all current treatments are looking at the wrong areas of the brain and therefore that is the reason all existing treatments fail so many sufferers.
What the researchers say
The new research shows that individuals with high levels of a little-studied neural receptor called GPR158 may be more susceptible to depression following chronic stress.
“The next step in this process is to come up with a drug that can target this receptor,” said the lead researcher. His team zeroed in on GPR158 as a player in depression after discovering that the protein linked to its specialized receptors, and thus to the gene, is elevated in people with major depressive disorder. To better understand GPR158’s role, the scientists studied male and female mice with and without GPR158 receptors.
Behavioral tests revealed that both male and female mice with active GPR158 receptors show signs of depression following chronic stress. On the flip side, suppression of GPR158 protects mice from developing depressive-like behaviors and make them resilient to stress.
Next, the researchers examined why GPR158 has these effects on depression. The team demonstrated that GPR158 affects key signaling pathways involved in mood regulation in the prefrontal cortex (the thinking and reasoning part of the brain), though the researchers emphasized that the exact mechanisms remain to be established.
The lead author explains that GPR158 is a so-called “orphan receptor” (which gets its name because its binding partner/partners are unknown) with a poorly understood biology and mechanism of action. GPR158 appears to work downstream from other important brain systems, such as the GABA system (GABA is the most prevalent neurochemical in the brain), a major player in the brain’s inhibitory control and adrenergic system involved in our reaction to stress.
“This is really new biology and we still need to learn a lot,” say the researchers.
The study also offers a potential clue to why some people are more susceptible to mental illness. Because mice without GPR158 don’t alter their behavior after chronic stress, the researchers concluded these mice were naturally more resilient against depression. Their genetics, or more precisely their gene expression, offer a layer of protection.
The researchers say this finding matches what doctors have noticed in people who have experienced chronic stress. “There’s always a small population that is resilient—they don’t show the depressive phenotype.”
As the search goes on for additional targets for depression, scientists are increasingly using new tools in genome analysis to identify orphan receptors like GPR158. “Those are the untapped biology of our genomes, with significant potential for development of innovative therapeutics,” the team says.
It’s well possible—indeed almost certain—that there are many genetic pathways to depressive illness. The genes that control the neurochemicals dopamine, oxytocin, serotonin and glutamate are all suspects which are “helping the (depression) police with their enquiries.” GPR158 is another. All of these genes are affected by stress and it could be that GPR158 in some way amplifies the effects of stressful events.
The other really fascinating point of this study is that it shows that resilience is largely inherited—an argument that I have been making in academic and business circles for over two decades.
(editor: if you want to read the first part of “The truth about depression (1nd part)“, please click here)
Dr. Bob Murray
Major depressive disorder and other stress-related mental health issues affect about 30% of lawyers according to a number of recent studies. About the same percentage contemplate suicide at least once every year. It is arguably the world’s greatest killer. It is the dark shadow lurking behind much heart disease, cancers, suicides, dementia, accidents, blindness, isolation and a range of other potentially fatal ailments.
No firm anywhere in the world can fail to be affected by the disorder, yet few are prepared to take any effective action to reduce the stress that is at the root of so much of it.
The truth is that we don’t know very much about the etiology of depression. Most so-called cures—antidepressants, psychotherapy and the rest—have little, if any, lasting effect on it and even that little is confined to a very few of the cases of major depressive disorder (MDD) or generalized anxiety disorder (GAD).
There are some recent studies that show that some lifestyle changes can help. For example, the British Medical Council’s Journal and in the journal Health Promotion International both showed that the so-called Mediterranean diet—lots of fish, legumes, whole grains and olive oil and very little red meat, sugary things and processed foods—reduced depression by 45% in the majority of people suffering from MDD. A brief summary of these studies can be found in a recent Medscape.
One new study also suggested that one hour a week of any kind of exercise could go a long way to preventing depression. An earlier study came broadly to the same conclusion but added that if the exercise was done in the company of a friend it was much more effective.
But such studies, potentially useful as they are, are either irrelevant to many people who work in law. Either they can’t follow their recommendations or never get time to read them.
The painful truth is that for the last 30 years no major drug company has carried out any research into cures for depression. Instead they still peddle SSRIs (selective serotonin reuptake inhibitors) which virtually every bit of research says don’t work.
Since depression affects so many lawyers and thus reduces the income of so many so many law firms it seems worthwhile to have a look at some of the recent research into this most prevalent of mental afflictions.
What the recent science says
Let me start by saying that nearly all researchers see depression not as a single illness, but rather what is called a “syndrome,” a collection of rather similar symptoms that have no single common cause. For a start we know that about 30 – 40% of depression is genetic. We also know that there is no single neurochemical problem connected with it—certainly not the inability of certain specialized cell receptors to “uptake” serotonin effectively. Rather depression has been linked to the malfunctioning of a number of neurochemical systems—dopamine, oxytocin, cortisol and glutamate (low or high blood sugar reactions) are the prime culprits. Mood disorders—of which depression is one—can also be caused by the activity and the mix of the microbiota in our gut. And of course, there’s workplace stress, childhood abuse, neglect, criticism, overly high expectations etc.
Depression is also the most misdiagnosed of all psychiatric illnesses. Studies have shown that most physicians—even many psychiatrists—are unable to spot it accurately. It is most often confused with bipolar disorder (manic depression), panic disorder, hypoglycemia, ADHD, chronic fatigue syndrome, thyroid disorders and quite a few other mental and physical problems.
Over the last few years we’ve found that men and women have differing symptoms of depression. Depression was under-diagnosed in men because we used to assume that the symptoms that women displayed were universal. They’re not, men can display quite different ones.
The following studies have been published over the last few weeks. There have been many others, but these are perhaps the most significant.
Stress, depression and memory decline
Undoubtedly the most important study on depression for a very long time was published a month ago. For the first time the causal link was established between stress—in our time this is mainly work stress—and depression.
Depression is associated with impaired recollection. People who are depressed have poor memory for positive events, and enhanced memory for negative events, but the relevant neural mechanisms are poorly understood. This is the focus of a new study in the journal Trends in Neurosciences.
What the researchers found
Stress is a common trigger for nearly all initial depressive episodes, and chronic (ongoing) stress can prevent new cells being formed in the hippocampus—the brain’s memory center—to replace those that have died off. They found this stress can also inhibit mesolimbic dopamine neurons (thus prevent sufferers from feeling pleasure) and sensitize the amygdala’s response to negative information. The amygdala is the main fear center of the brain and this sensitization tends to make people feel anxious and fearful and more likely to look for what’s wrong rather than what’s right.
As our society becomes increasingly stressful the rate of depression increases. Some recent studies have shown that up to 30% of US employees suffer from episodes of major depression. That is up from about 8% or so fifteen years ago. The stress produced by the way we are forced to work— including open plan offices and the like, the fear of job loss, the isolation of working from home, over work, being “on” via smartphone 24/7—is a major stressor. We are simply not designed to cope with it. Now we know for sure that this is, quite literally, killing us through the stress/depression nexus (often disguised as psychosomatic illness or very real heart disease).