Bipolar Spectrum Disorders in DSM-V
September 2, 2010
Question:
"What will be the representation of the Bipolar Spectrum Disorders in DSM-V?"
Rakesh Jain, MD, MPH:
There is no doubt that the single most discussed, argued over, and controversial topic is what you are alluding to—What will DSM-V do with the Bipolar Spectrum Disorders!
This question was asked at the recent Treating the Whole Patient: The Mind Body Connection in Psychiatric Disorders all day CME meeting in Newport Beach, Calif. If you were there, you received exposure to a tremendous amount of cutting edge, practical information. And if you were not there, fret not—we are going to conduct an even more expanded CME program at the 23rd Annual U.S. Psychiatric and Mental Health Congress in Orlando, Fla., from November 18th to the 21st. I hope you will come attend.
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Thought and Mood Disorders Continuum
August 26, 2010
Question:
“Please comment further on the history of the dichotomy between schizophrenia and bipolar disorders.”
Jon W. Draud, MD, MS:
This will be a brief posting that will begin to answer the above question, and will be expounded over the next few months seeing as there are so many aspects to be explored. The distinction between so called “thought and mood disorders” dates to the late 1800s and is otherwise known as the Kraepelinian dichotomy. Emil Kraepelin established this categorical division in 1880, but interestingly recanted his own thinking in a book published in 1920—six years before his death.
I happen to fall into the camp who believes there is no real clear-cut division and that thought and mood disorders are better capitalized along a continuum. As mentioned, we will explore this continuum concept in detail over the coming months, but for now will mention a few thoughts on the scientific basis for establishing a bonafide psychiatric disease state. In a recent paper, Lake lists six criteria that must be met to establish the existence of psychiatric diseases, given that there are no discreet pathophysiological tests that are diagnostic.1 The criteria are: 1) symptoms that are clearly unique to one disease; 2) consistent epidemiology; 3) consistent response to medications; 4) generally consistent course and outcome; 5) an increased heritability in first-degree relatives; and 6) the identification of specific genetic susceptibility loci.
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Depression and Inflammation: Part 2
August 19, 2010
Question:
"Is major depression an inflammatory disease?"
Vladimir Maletic, MD:
Last month we discussed the role of inflammation on the etiology and clinical presentation of depression. We will now focus our attention on an even more controversial topic: Is major depression, at least in part, a somato-psychiatric disease? In other words, do inflammatory mediators released in the course of the depressive episode directly shape neuropsychiatric symptoms of depression, and participate in functional and structural remodeling of the brain?
Let’s review some available evidence. Patients suffering from depression tend to have substantially elevated peripheral levels of inflammatory cytokines (typically interleukins: IL-1, IL-6, or tumor necrosis factor-alpha).1,2 Elevation of inflammatory mediators is a nonspecific response, commonly observed in stressful situations, even in healthy individuals.3 What sets patients with depression apart from healthy, but “stressed-out,” individuals is the lack of anti-inflammatory response (mediated by IL-10).4 Functional imaging studies indicate that peripheral inflammatory cytokine elevation tends to be associated with activation of similar brain areas as the ones implicated in depression, pain, and stress response (amygdala, subgenual anterior cingulate [sACC], insula, and dorsolateral prefrontal cortex [DLPFC]).2 As a matter of fact, in a group of recently vaccinated healthy individuals, elevation in peripheral inflammatory cytokines, and ensuing changes in brain activity were associated with fatigue and impaired concentration.5 In a separate study of patients with depression, Alesci and colleagues found that elevation of plasma IL-6 directly correlated with core symptoms of depression, such as sadness, guilt, fatigue, difficulty concentrating, low self-esteem, and even suicidal ideation!6
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Measuring Remission
August 12, 2010
Question:
"I know Remission is the goal of treatment in major depression, but how do I know when I am there?"
Rakesh Jain, MD, MPH:
This is a simple sounding question, but you clearly have articulated a concern in the field: How do we define remission, and how do we measure it? If we don’t answer these questions, then remission remains just a highfalutin concept and not a reality for all of our patients. This would be unacceptable, of course. So let’s have a heart-to-heart conversation regarding your very important question.
The most widely accepted definition of remission is the one used in most research studies, i.e., a patient achieving a score on the HAM-D-17 scale (17-item Hamilton Rating Scale for Depression).1 This is a woefully inadequate definition as a score of 7 or less could very much indicate that there are still some symptoms of depression left over. Also, what about patient’s functioning? Is that not as important as measuring symptoms of depression? The HAM-D-17 does not measure functional improvement. So, is it then appropriate to use only a score of 7 or less on this scale, a scale that does not even measure restored functioning as a measure of Remission? To top it off, use of scales and screeners in clinical practice is not a routine, and even the use of DSM-IV criteria is not a routine clinical practice.2,3
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Biological Test for Depression
August 5, 2010
Question:
"Why doesn’t psychiatry use the serial levels of BDNF and the cytokines as strong markers for the diagnosis of depression and in the assessment of the effectiveness of treatment as it is done for cardiac enzymes in the diagnosis of MI?"
Charles Raison, MD:
I am glad you asked this question because it actually touches upon what I consider to be the central conceptual shift we need to make in our understanding of psychiatric disease, in general, and major depression, in particular. As a start to answering this, let’s ask another question: Why would we want to get serial levels of bodily chemicals, such as BDNF (brain-derived neurotrophic factor) or cytokines? If you think about it for awhile I suspect you will agree that the only reason to go through all the trouble would be because measuring the chemicals would tell you something you can’t “see with the naked eye.” What sort of questions would be important for any blood test for depression to answer? In general, three things: 1) Does the patient have a certain illness; 2) Is there a specific treatment that would be best suited to this particular patient; and 3) What is this patient’s prognosis—what can she or he expect from the disease?
Let’s start with the first question. The hope that someday we’ll have a blood test for depression is one of the longest-standing fantasies of our field. I want to suggest that it is profoundly misguided because it really misunderstands the type of entity depression is. Can you cut depression out of a person like a tumor and show it to me? Of course not. It is a probabilistic syndrome. It is a chronic tendency for a person to experience dark emotions, loss of interest, and any of a number of related cognitive and neurovegetative symptoms. There is no depression underlying the symptoms: it is the symptoms. If a person has the symptoms, they are depressed by definition. If this is so, why would you need a blood test to confirm what you can see with your own eyes? Suppose a person came to your office weeping, crying, filled with pathological guilt, and a host of neurovegetative symptoms anxious to kill himself/herself and end his/her misery. If there was a blood test for depression and it was negative, would you send the patient away untreated?
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HPA Axis and Suicide
July 29, 2010
Question:
“You mentioned a link between the HPA axis and suicide in your Treating the Whole Patient presentation at the 2009 Psych Congress. Please comment further on this.”
Jon W. Draud, MD, MS:
Yes, this is an interesting finding and is discussed in detail by Jokinen and Nordström.1 Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has long been associated with patients suffering from major depressive disorder, but studies linking HPA hyperactivity and suicide are less numerous and consistent.
Jokinen and Nordstrom evaluated 36 inpatients under the age of 30 with (n=18) and without suicide attempt at the index episode. It has been shown that non-suppressors of the dexamethasone suppression test (DST) are more likely to commit suicide, and the results in this study seem to confirm that. According to the authors, the DST non-suppressor rate was 25%. They found that DST non-suppression was associated with suicide attempt and post-dexamethasone serum cortisol at 11:00 pm was higher in suicide attempters compared to those who did not attempt suicide. Overall, the DST non-suppressor rate was 39% in those who attempted suicide versus 11% in those who did not attempt suicide. These results add to the established body of literature that supports a link between hyperactive HPA and suicide attempts. There were no observed gender differences in the study and this is consistent with previous findings.
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Depression and Inflammation: Part 1
July 22, 2010
Question:
"Is major depression an inflammatory disease?"
Vladimir Maletic, MD:
I believe that we have strong evidence that inflammation is a relevant pathophysiological mechanism contributing to the development, severity, and persistence of major depression (MDD).1,2,3 Is it not the same as saying that MDD is an inflammatory disease? Not, exactly. Rheumatoid arthritis and ulcerative colitis would be good examples of inflammatory disorders. Inflammation is the fundamental mechanism of etiopathogenesis in these conditions and the primary target of successful treatments. By comparison, inflammation has a significant role in etiology and propagation of malignant disorders. Yet cancers are not commonly considered as a primarily inflammatory condition, nor are the anti-inflammatory agents the mainstay of treatment.
Let us now examine the evidence linking depression and inflammation. Stress and medical illness are the principal precipitants of depression, both are associated with immune activation and elevated inflammation.1,3 Compromised cortico-limbic regulation of mood and stress response appears to be the central feature of a depressive episode, most likely giving rise to neuropsychiatric symptoms of depression.1,3 The brain responds to a depressed state in a manner that is very similar to a moderate “fight or flight” response: inadequate hypothalamic-pituitary-adrenal regulation, sympathetic activation combined with diminished parasympathetic tone, and, lastly, inflammation!1,3
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Treatment-Resistant Depression
July 8, 2010
Question:
"Is it ever appropriate for me to tell my treatment refractory patients: ‘There’s nothing more that can be done to help you’?"
Rakesh Jain, MD, MPH:
Let me respond by telling a recent, personal story. My sister-in-law was diagnosed with lung cancer two years ago and despite initial success in treatment, the cancer came back aggressively. She was taken care of by one of the finest oncology teams anywhere in the United States. Multiple treatments were tried—alas, no success. Her health deteriorated remarkably, and her quality of life fell sharply.
We were asked by the doctors to consider stopping treatment and offered hospice care. They told us that, realistically speaking, my sister-in-law’s chances of survival beyond four weeks were less than 1%. We were told her condition was treatment- refractory, and they had no more to offer.
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Omega-3 Fatty Acids for Mood Disorders
July 1, 2010
Question:
"Any data yet on using “immune stabilizing” vitamin/dietary supplements as antidepressant adjuncts?"
Charles Raison, MD:
This is a great question, and the short answer is that there are all sorts of data around this issue, especially regarding the use of omega-3 fatty acids for mood disorders. As with all things psychiatric, the data are mixed with both positive and negative studies, but lest this dissuade us from seriously considering the potential benefits of these compounds, we would do well to remember that only 50% or so of all the antidepressant studies conducted over the years have beaten placebo.
Omega-3 fatty acids are not the only vitamin/dietary supplements with anti-inflammatory properties that might benefit depression. Much can be said about vitamin D in this regard—and will be said in my next Q&A when I answer a question about vitamin D in particular. For this month, given their potential and the extent of the available data let’s focus on omega-3s.
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The Brain, Depression, and Remission
June 24, 2010
Question:
"I have been reading that depression can be harmful to the brain. Is this true, and is remission protective to the brain?"
Rakesh Jain, MD, MPH:
You are right, there has been a recent explosion of knowledge in the field regarding the adverse effects of major depression on the various structures of the brain. We have long known that major depression hurts psychological well-being and physical health. Now we are realizing there is one more thing to worry about.
That worry is the impact of depression on both the structure and functioning of the brain.
Let’s first quickly review the evidence. It appears that major depression is much more than just an ‘emotional’ disorder, because significant biological events occur when someone is ‘just’ depressed. These events include (but are not limited to) hypothalamic-pituitary-adrenal (HPA) axis dysregulation, autonomic dysregulation, neurotrophic dysregulation, and inflammatory cytokine dysregulation.1,2 All of these factors (and many others we don’t yet know about) collude to create structural and functional harm to the brain.3-6 In and of itself, structural changes are worrisome, but it’s the related cognitive-emotional deterioration that makes these issues important to every clinician.7,8
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The Role of Glia in MDD, Have We Been Missing it All Along?
June 17, 2010
Question:
"Is it true that glia cells are the primary brain cell group impacted by depression?"
Vladimir Maletic, MD:
We have unjustly neglected the role of glia cells in neuropsychiatric conditions for a long time. Accumulating evidence suggests that glia cells may be implicated in major depressive disorder (MDD)-related pathology.1-8 The human nervous system has approximately 100 billion neurons and one trillion glia cells, making them an overwhelming majority.
Three families of glia cells have very different roles and histological origin. Astroglia are co-partners with neurons in neural transmission and provide structural support. Oligodendroglia are involved with myelination of white matter tracts connecting various components of brain circuitry. Microglia are the main immune cells of the brain; they are of mesodermal origin unlike astroglia and oligodendroglia, which are of ectodermal origin.1,2,8
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Physical Illness in Patients with Recurrent Depression
June 10, 2010
Question:
“Please comment further on the increased prevalence of physical disorders in patients with recurrent depression.”
Jon W. Draud, MD, MS:
There have been many studies evaluating the prevalence of depression in those with medical illnesses, but few have examined the rates of physical illnesses in those with defined recurrent depression. Farmer et al.1 studied a large case-control group evaluating physical illnesses in those with or without recurrent depression. They also measured body mass index (BMI) since many medical disorders are related to obesity.
Participants who were included had two or more episodes of major depression of at least moderate severity and were interviewed by trained psychologists in graduate school. It was a relatively pure “depressive” sample in that participants were excluded if the depression was substance related secondary to medical illness or if there was a family or personal history of schizophrenia or bipolar illness.
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Effect of Spirituality on Inflammatory Response and Depression: Part 2
June 3, 2010
Question:
"What effect does spirituality have on decreasing the inflammatory response and depression?"
Charles Raison, MD:
In April I discussed spirituality and inflammation, focusing on research by our group at Emory on the effects of compassion meditation on inflammatory responses to psychosocial stress.1,2 This month we turn to the thornier question of how spirituality relates to depression.
The first thing to say about this issue is that concepts such as “spirituality” and “religion” are very broad and encompass a wide range of emotions, beliefs, and behaviors. Religion has brought us the inquisition and the Dalai Lama.
Given that religion and spirituality have both very bright and very dark faces, it shouldn’t be a surprise that taken as a whole they seem to both protect against, and promote, the development of depression.3 Despite the complications, if one looks through the many studies that have examined this issue, a clear pattern emerges.
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Bipolar Disorder in Children and Adolescents
May 26, 2010
Question:
"Is bipolar disorder a ‘real’ condition in children and adolescents? I hear so much controversy surrounding this issue in the press and would appreciate your clarification."
Rakesh Jain, MD, MPH:
I received A LOT of questions on this topic at the 2009 Treating the Whole Patient program presented at the U.S. Psychiatric and Mental Health Congress. If there is one controversial issue in the world of mental health, this is it! The single most controversial issue in psychiatry is articulated in your question, and it deserves close examination from us clinicians.
First of all, it’s important to remember that DSM-IV does not tell us that there is any age limit to making a diagnosis of bipolar disorder. From the point of view of what our major diagnostic text tells us, there is no prohibition from making the diagnosis in any age group as long as the criteria are met.
Why then this controversy? None of us question if major depression or panic disorder belongs exclusively in the domain of adulthood, then why is there such concern about BD?
This may be for multiple reasons.1,2 Bipolar disorder has only in the last two decades or so been fully appreciated as a common psychiatric condition in both psychiatrists’ and primary care physicians’ offices; some years behind major depression achieved such recognition. Could this then be the reason why we are slower to come to the appreciation of BD’s existence in individuals under 18 years of age?
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Depression Following Myocardial Infarction
May 19, 2010
Question:
Could you please comment further on the data presented in the slide titled “Survival Curves for Non-Depressed Versus Depressed Participants”?
Jon W. Draud, MD, MS:
This is a great question and the slide is taken from a paper by Carney et al.1 We have known that depression is a risk factor for mortality following an acute myocardial infarction (MI).2-4
However, most studies of depression and mortality post-MI have only followed patients for 12 months or less. Seeing as depression is generally chronic, Carney et al. postulated that the adverse effects may linger for many years so they studied a cohort of patients for five years after MI. The other unique aspect of this study was that it was based on interview diagnosis of depression as opposed to traditional measures, which rely on self-reporting tools like Beck Depression Inventory (BDI) scores. Several studies have used self-report inventories to evaluate depression and MI.5-8
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Depression and Diminished Capacity for Pleasure
May 12, 2010
Question:
"Is there any objective neurobiological evidence indicating that depressed patients have diminished capacity for pleasure?"
Vladimir Maletic, MD:
The short answer is: most likely. In a very simplified view, the "limbic triangle" composed of amygdala, n.accumbens/ventral striatum complex, and hippocampus is involved in providing a running emotional commentary on perpetual changes in our external and internal environment. Amygdala responds to novelty, especially dangerous and threatening signals. In contrast, n.accumbens, also a "novelty detector," tends to preferentially respond to joyous, rewarding events. Amygdala and n.accumbens compete for hippocampal "attention." After "sifting" through the inputs, hippocampus generates an emotional association related to the recent event that is subsequently stored in contextual memory. This is an ongoing, reiterative process influenced by constant flow of sensory information from thalamus and integrative cortical areas. If emotions are confusing or incongruent with our expectations, the signal may be forwarded for secondary processing to higher cortical areas. Emotions may be interpreted as an impetus, a homeostatic signal capable of eliciting a suite of adaptive behavioral response.
In major depressive disorder (MDD) emotions may lose some of their adaptive value. Individuals with depression become steeped in misery and dejection, often accompanied by morose rumination. Adaptive exchange with our environment is disrupted; depression takes over as the conductor of our limbic orchestra. Thus, our mood state, rather than ongoing interaction with the environment, becomes the principal determinant of our emotions.
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Depression and Bone Loss
May 5, 2010
Question:
"Please comment further on the section of your talk dealing with depression and bone loss."
Jon W. Draud, MD, MS:
This question relates to studies by Diem et al.1 and Yirmiya et al.2 from my presentation at the 2009 U.S. Psychiatric and Mental Health Congress. First, Diem et al.1 examined 4,177 women aged 69 and older from the Study of Osteoporotic Fractures. Depressive symptoms were measured by the Geriatric Depression Scale (GDS), and patients were categorized as depressed if their GDS score was ≥6 at the fourth examination. Bone mineral density (BMD) of the total hip and two subregions (femoral neck and trochanter) were measured at two exam points (fourth and sixth examinations) using Hologic scanners. Because it has been thought that some antidepressants have direct effects on bone metabolism, patients using antidepressants were excluded.
Overall, women with higher depression scores showed higher age-adjusted annualized percentage loss of bone density at the total hip than women with a GDS score ≤6. Similar findings occurred related to decreased bone density at the femoral neck, but not the trochanter. This is clinically significant because of the higher rates of fracture in elderly patients with depression. There are many possible reasons for the association, including decreased physical activity in elderly patients with depression, increased weight loss, increased smoking, and other medical illnesses like diabetes; chronic obstructive pulmonary disease and liver disease may also increase depression rates.
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Effect of Spirituality on Inflammatory Response and Depression: Part 1
April 28, 2010
Question:
"What effect does spirituality have on decreasing the inflammatory response and depression?"
Charles Raison, MD:
I’m glad to get a chance to answer this question because I probably know about as much regarding this topic (or at least the inflammation part of it) as anyone on earth. Based on this expertise I can assure you that we don’t really know the answer! In fact, I suspect there probably isn’t a single answer. I’ll focus on one answer in this month’s discussion, which focuses on our research on compassion meditation and inflammatory responses to stress. Next month, I’ll focus on what we know regarding spirituality and depression. But before I do this let’s talk about the issue more generally.
Here is the rub. Spirituality is a very broad term that covers multiple domains. Moreover, from a physical and mental health point of view, there are good and bad types of spirituality. For example, studies have shown that belief in a vindictive God is associated with increased mortality.1 If you believe in a just and vengeful God, data suggest that you will die sooner than if you believe in a good old guy in the sky, or even in nothing.1 Consistent with this, many measures of mortality and overall health are worse in U.S. states with a high prevalence of fundamentalist Christian religion when compared to more secular states.2 I could go on…Christian Scientists who don’t believe in accepting modern medical treatment die a number of years sooner than the average American3…and so on.
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Pseudounipolar Depression
April 21, 2010
Question:
"I have recently heard a lecture about "pseudounipolar" depression. Does this form of mood disorder really exist?"
Vladimir Maletic, MD:
Unfortunately, there is a lack of consensus about the existence of "pseudounipolar" depression. Many patients who are diagnosed as depressive disorder NOS or treatment-resistant depression, display a combination of depressive symptomatology combined with two or more hypomanic/manic symptoms, yet they do not meet syndromal criteria for any other mood state. Most frequently patients will complain of depression, social anxiety, obsessive tendencies, irritability, emotional liability, "crowded mind" and difficulty falling asleep because their mind "will just not turn off."
Our diagnostic taxonomy offers little help; unipolar and bipolar depression have the same criteria. Therefore, one must rely on information about mania or hypomania to make the distinction. Patients will seldom spontaneously report hypomanic symptoms; sometimes it is due to lack of awareness, at other times it is reluctance to discuss embarrassing behaviors from the past.
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Wellness and Depression
April 14, 2010
Question:
"I have been reading about the concept of Wellness. Does this have a role in my practice (I take care of a lot of folks with depression)?"
Rakesh Jain, MD, MPH:
The World Health Organization boldly states that health is "A state of complete physical, mental and social well-being and not merely the absence of disease or infirmity."1 This then raises the obvious questions: Are these lofty and unreasonable goals, or is Wellness a basic human right that all should strive for, regardless of whether they suffer from depression or not?
C. Robert Cloninger, MD, from the department of psychiatry of the Washington University School of Medicine recently wrote: " Psychiatry has failed to improve the average levels of happiness and well-being in the general population, despite vast expenditures on psychotropic drugs and psychotherapy manuals. " 2
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Anxiety, Depression, and Pain
April 7, 2010
Question:
"Several of my depressed patients report worsening of their pain symptoms with exacerbation of anxiety and depression. What is the connection between anxiety, depression, and pain?"
Vladimir Maletic, MD:
The overlap of anxiety, depression, and pain is more a rule than an exception. Epidemiologic studies suggest that 30% to 60% of patients with depression also suffer from a painful condition. Presence of pain is a major predictor of depression and anxiety. A group of authors reported a type of "dose-response" relationship: the more bodily regions impacted by pain, the greater the prevalence of generalized anxiety disorder and major depressive disorder (MDD).1 Furthermore, symptom severity in depression, anxiety, and sleep disorders predicted onset of chronic widespread pain in a 15-month prospective study.2 It is becoming clear that the relationship between MDD, anxiety, and pain runs far below the surface.
Brain circuitry involved in regulation of emotions and stress response, to a significant degree, overlaps with components of the "pain matrix" involved in emotional and cognitive aspects of pain processing. Having in mind the evolutionary value of pain, stress, and emotions–mobilizing the organism to organize and execute an adaptive response–it would not be a surprise if nature, parsimoniously, selected overlapping pathways.3
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Depression and Thermoregulation
March 31, 2010
Question:
"Would you try fever therapy for inflammation/depression (i.e., sauna "fibrogenics")?"
Charles Raison, MD:
This question is insightful, but it also demonstrates a very common confusion about two very distinct states—in this case hyperthermia and fever. Before I answer the question, let's do a quick review of hyperthermia. Then we'll talk about what fever is, what causes it, and what it is for.
Let's start with the sauna. Many of us find saunas, steam rooms, and hot tubs to be relaxing. But let's think for a moment about what they do. Each of us has the equivalent of a thermostat in our brain and spinal cord. Most of the apparatus resides in the hypothalamus, a brain region essential for the brain's control of all types of circadian rhythms.1 This thermostat likes to keep the body at an average temperature of 37° C or 98.6° F. But the thermostat has its own daily rhythm that keeps the body cooler at night during sleep and warmer during the day during wakefulness, with a peak temperature in the late afternoon early evening.
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Neurobiology of Psychotherapy
March 24, 2010
Question:
"Is therapy, such as cognitive-behavioral therapy, helpful only through psychological means, or is there a biological basis to such treatment?"
Rakesh Jain, MD, MPH:
Psychotherapies quite clearly are nonpharmacological interventions, yet they seem to pack a powerful biological punch! This is quite a revelation for clinicians no matter what school of thought they belong to—be it purely biological or purely psychological views of depression. It is becoming very obvious that medications help not just through their effects on neurobiology but by also affecting a patient’s belief systems, which in turn exerts a powerful benefit to the individual’s neurobiology. This has been demonstrated by the positive neurobiological changes that occur in patients who receive a placebo medication. In other words, there is a positive, circular relationship between positive psychological changes and positive neurobiological changes.
Psychotherapy has clearly been demonstrated to help with depression. For decades we believed this occurred as a result of changing thought patterns. Now, this is true, but the untold story is about the neurobiology of psychotherapy. This is completely changing how we view how therapies help individuals. Let’s quickly review some recent relevant studies in order to explore this issue.
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Adverse Childhood Events and Risk of Autoimmune Diseases
March 17, 2010
Question:
"I was very intrigued by the slide you presented on Adverse Childhood Events and Future Risk of Autoimmune Disease and wondered if you could explain the study in more detail."
Jon W. Draud, MD, MS:
Thank you for a great question. This was an alarming paper to read and I highly recommend it to you and others following our Community Forum. It pertains to a slide in my presentation at the 2009 U.S. Psychiatric and Mental Health Congress and is based on a paper written by Dube et al.1 The aim of the study was to determine whether traumatic stress in childhood would increase the adult risk of developing autoimmune diseases. It was a retrospective study looking at 15,357 adult patients enrolled in an HMO and the Adverse Childhood Experiences (ACEs) Study. ACEs could have been childhood physical, emotional, or sexual abuse; witnessing domestic violence; and growing up in a household with substance abuse, mental illness, parental divorce, and/or an incarcerated household member. The total number of ACEs was then scored (0-8) and used as a measure of childhood stress. Patients were studied to see how many hospitalizations due to 4 rheumatic or 21 selected autoimmune diseases occurred.
The results were quite dramatic, I think, in that 64% reported at least one ACE and the event rate per 10,000 patient years for first hospitalizations was 31.4 in women and 34.4 in men. Furthermore, first hospitalizations for any autoimmune disease increased as the number of ACEs increased.
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HCV and Depression
March 10, 2010
Question:
"By treating people with antidepressants who are taking interferon for hepatitis are we interfering with halting the virus?"
Charles Raison, MD:
This is a great question that shows a good grasp of immunology. We give people with hepatitis C virus (HCV) infection interferon (IFN)-alpha because, as a proinflammatory cytokine, IFN-alpha activates the immune system to better rid the body of the virus. Many studies suggest that antidepressants reduce inflammatory signaling. If they do this, maybe they interfere with the action of IFN-alpha, which would lead to a terrible irony. People would feel better on an antidepressant but at the price of going through the miseries of IFN-alpha for nothing, or at least a better chance of a bad outcome.
The answer is—unfortunately—that no one knows.1 Our group was involved in planning what would have been a huge study testing this issue. This study was actually designed to show the opposite—that antidepressant pretreatment would improve viral outcomes because people would be more likely to be able to stay on IFN-alpha as a result of improved side-effect burden. We spent the better part of a year working on it, but it was killed at the FDA, and with that the opportunity to perform a really rigorous examination probably vanished for all time.
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Five Traits of a Good Clinician
March 3, 2010
Question:
"What traits in us, the clinicians, affect outcomes in our depressed patients?"
Rakesh Jain, MD, MPH:
This is very well thought out question and I welcome the chance to engage in a dialogue with you and our other readers! We clinicians often talk about patient traits that affect depression outcomes, such as length of depression, number of previous episodes, etc. We also often talk about the capabilities of different pharmacologic and nonpharmacologic treatments, such as how quickly do the interventions work, how effective is it, how does it compare to previous therapies, etc. These are, of course, extremely important questions to ask. But, what we tend to under discuss is what about us, the clinicians, as a variable in affecting patient outcomes. What personal traits, habits, and belief systems in us, the clinicians, affect our patients’ outcomes? Do you agree with me that this is often not discussed?
I am certain you have your own opinions on this issue, and I do too. A study by Schattner and colleagues1 examined the issue of which physician traits do patients desire in a ‘good physician.’ Traits patients reported as highly desirable include professional expertise, patience and attentiveness, informing the patient, representing a patient’s interests, being truthful, and respecting the patient’s preferences.
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Genetic Contribution in MDD
February 24, 2010
Question:
"What is the extent of genetic contribution in MDD? I thought that it was mostly a stress-induced condition."
Vladimir Maletic, MD:
Major depressive disorder (MDD) is believed to be a product of interaction between several vulnerability genes and environmental adversity (this includes stress, trauma, and also medical illness).1
There are differing opinions about the relative contribution of genes versus environment. Before one broaches the topic of etiopathogenesis, it would be prudent to clarify the definition of MDD as a diagnostic category. Recent research suggests that MDD is not a single biological entity, but rather a grouping of biologically diverse conditions with similar symptomatic manifestations. Therefore, any statement made about the origins of MDD is by necessity probabilistic: it may apply to a significant number of individuals afflicted by MDD, but certainly not to all of them.1
The body of genetic research into origins of MDD would indicate a strong influence of heritability. While estimates of heritability range from 30% to 50%, it is clear that environment has at least an equal, if not greater, contribution.2 Genetic pattern of MDD inheritance is a very complex one. Vulnerability towards MDD is conferred by interactions of multiple different genes with differing magnitude of effect. Estimates vary from dozens of genes with moderate-to-mild effect on one end, to a cumulative impact of thousands of genes with minor individual contributions at the other extreme. Research into MDD genetics is further confounded by complicated gene interactions (a process also known as epistasis): two “vulnerability” genes may have a synergistic effect, amplifying each other’s influence, or their contributions may cancel each other out!1
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Bridging the Brain to the Body
February 17, 2010
Question:
"Could you please comment further on the quote you cited by Dr. Charles Mayo and how the concept of the progressive nature of neuropsychiatric illnesses bridges the brain to the body?"
Jon W. Draud, MD, MS:
This is an excellent question that gets to the heart of our evolving concept of the mind-body science. Dr. Mayo’s astute quote was from 1898 and underscores that for over 100 years physicians have suspected a strong link between the brain and the body. The quote reads: "Worry affects the circulation, the heart, the glands, the whole nervous system. I have never known a man who died of overwork, but many who died from doubt." We clearly see that Dr. Mayo was an early adopter of how profoundly disturbances of the mind could impact bodily functions in the periphery. This is particularly salient given that Western medicine has spent years artificially disconnecting psychiatry and the brain from general medicine and the body.
This concept was explored in my presentation from the 2009 U.S. Psychiatric and Mental Health Congress (USPC). Carney and colleagues1 showed that depression is an independent risk factor for death in a 5-year, follow-up study that examined survival in patients without depression versus patients with depression post-myocardial infarction. The results are impressive and show that the presence of either major or minor depression increases one’s risk for all-cause mortality.
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vmPFC Activity in MDD
February 10, 2010
Question:
"Is the increased activity in vmPFC in major depressive disorder (MDD) a function of loss of volume, as an adaptive mechanism, or is it a separate mechanism?"
Vladimir Maletic, MD :
The challenge in answering this question starts with the definition of vmPFC. Some authors define vmPFC (ventromedial prefrontal cortex) as a structure inclusive of BA (Brodmann Area) 11, 25, and 32; others limit it only to 11 and 32. Distinction is relevant because BA 25 is commonly considered to be the subgenual anterior cingulate cortex (sgACC). Although both of these areas have rich bidirectional connections with limbic areas, especially the amygdala, there are also notable functional differences.
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Adjunctive Anti-inflammatory Treatment and Depression
February 3, 2010
Question:
"Would use of adjunctive anti-inflammatories be useful for depression?"
Charles Raison, MD:
The short answer to this question is maybe. I know of two randomized, placebo-controlled studies showing that the addition of the COX-2 inhibitor celecoxib significantly increased response to a noradrenergic and to a serotonergic antidepressant.1,2 I also know of open data suggesting that the addition of 380 mg/day of aspirin to SSRIs converts nonresponders to responders.3,4 Several studies suggest that cortisone may improve depressive symptoms and be of benefit for conditions highly comorbid with depression, such as chronic fatigue syndrome,5,6 and in patients with autoimmune disorders, several studies confirm that tumor necrosis factor (TNF)-alpha antagonists, such as infliximab or etanercept, have antidepressant properties.7,8
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Cardiovascular Disease and Depression
January 27, 2010
Question:
"Could you please comment further on the relationship between depression and cardiovascular disease?"
Jon W. Draud, MD, MS:
This is an excellent question that underscores the mind-body connection we sought to explore at the 2009 U.S. Psychiatric and Mental Health Congress (USPC) in Las Vegas. The connection between depression and cardiovascular illness is quite robust and there is a wealth of literature to support it. Essentially, due to a hyperactive hypothalamic-pituitary-adrenal axis we believe that there are alterations in the periphery of cytokine levels, cortisol levels, and catecholaminergic tone. This primes the heart and other organ systems for numerous diseases.
I would like to examine several of the studies referenced at USPC to illustrate the point further. First, Whang and colleagues1 looked at over 63,000 patients and illustrated a correlation between depression status and sudden cardiac death, fatal coronary disease, and non-fatal myocardial infarction (MI).
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Exercise and Depression
January 20, 2010
Question:
"As a mental health professional, what should I know about physical exercise when I am treating my patients with major depression?"
Rakesh Jain, MD, MPH:
Even though mental health professionals are known as‘mind’clinicians, over the last decade published studies have shownthat we are the quintessential mind-body clinician. Emerging data on the use of physical exercise to treat depression powerfully reinforces this very message—that depression is a mind-body disease and treating it requires a mind-body approach.
We have long advocated physical exercise for our patients, but primarily for its clear and convincing positive benefits on physical health. You may be surprised to hear that the data on exercise’s effects on mental health are very significant too! In fact, the data is so impressive that I am beginning to recommend it to every patient with a mood disorder that I treat.
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