Posted by jrbecker on June 30, 2003, at 11:23:20
http://www.nytimes.com/2003/06/22/weekinreview/22KRAM.html?ex=1057118400&en=29185b1e48d1db2a&ei=5070
http://www.medscape.com/viewarticle/457165full texts of these articles...
>>>>>>>>>>>>>>>>>>>>
Your Zoloft Might Prevent a Heart Attack
By PETER D. KRAMERPatients are beginning to treat depression with respect. Whether their doctors are ready to do so is less clear.
A study in the current issue of The Journal of the American Medical Association finds that almost six in 10 Americans who suffer depression seek treatment in a given year. A decade ago, the figure was one in three.
But the researchers found that only about 40 percent of patients received what standard guidelines consider "minimally adequate medical treatment." Those criteria call for a month of antidepressants monitored in four office visits or eight half-hour counseling sessions.
There is a long tradition in general medicine of ignoring or undertreating depression. But a second article in JAMA suggested reasons that the pattern may change. That report described the largest study of psychotherapy ever conducted, sponsored by the National Heart, Lung and Blood Institute.
The study is a response to evidence, developed over the past decade, that depression, like diabetes and hypertension, is a risk to the heart. By middle age, studies show, depression triples or quadruples the risk of cardiac death. The most acute danger comes in the wake of heart attacks. After a first attack, depression raises the risk of recurrence dramatically — between two- and fourfold.
The recent study enrolled about 1,800 patients who had suffered a heart attack in the past month and now met criteria for depression. Half the depressed patients received cognitive psychotherapy, a treatment aimed at reversing self-disparaging thoughts. The other half received "usual care," without psychotherapy.
Despite the researchers' expectations, psychotherapy had no effect on the recurrence of heart attacks or on mortality. Therapy lowered the degree of depression early on; over time, the differences between the treatment and control groups vanished.
But hidden in the therapy trial results are suggestive findings about another standard intervention, antidepressants. For ethical reasons, if subjects had severe depression or if they failed to respond to psychotherapy, they were offered medication, principally Zoloft. By the end of the study, almost a quarter of the subjects had taken antidepressants for substantial periods of time.
Antidepressants were associated with an extraordinary reduction in death or heart attack recurrence — 30 to 40 percent. The treatment assignment was not random, which makes the result hard to interpret. But it was the more depressed, less responsive group who had gotten medication.
If antidepressants reduce cardiac risk, how they do so remains unclear. The connection between depression and heart disease goes beyond neglect of one's health. Recent studies have shown that people suffering from depression have subtle problems with heart rate regulation. And it has long been known that their blood platelets can be "sticky" — that is, likely to cause clots. The drugs used to treat depression by affecting the brain's use of the chemical serotonin — Prozac, Paxil, Zoloft — also tend to reduce the abnormalities in heart rhythm and blood clotting. For cardiac patients, these antidepressants may act primarily as blood thinners, a complicated form of baby aspirin.
However the drugs work, their role in treatment is becoming clear. Dr. Ranga K. Krishnan, chairman of psychiatry at Duke University and a consultant to the cardiac study, says that until contradicting data emerge, treatment with a medication like Zoloft is now the standard of care for patients with heart attacks accompanied by depression.
The relationship between cardiovascular disease and depression is especially intimate. Harm runs in both directions. Scans show that patients who develop depression late in life tend to have suffered "silent strokes" in parts of the brain that regulate mood. A region called the prefrontal cortex (just behind the forehead) is particularly implicated.
But depression extends into other realms of internal medicine. Chronic depressives may have enlarged adrenal glands, brittle bones and a diminished ability to fight off infections. Interferon — a standard treatment for hepatitis C, some cancers and multiple sclerosis — causes depression with high frequency. In one study, giving two weeks of Paxil before starting interferon cut the depression rate from 45 percent to 11 percent, with a corresponding decrease in the treatment dropout rate. Dr. Krishnan, believes that it is only a matter of time until large numbers of non-psychiatric doctors gain experience in treating depression.
Brain scans suggest that like silent strokes, interferon may exert its harm by impeding the workings of the prefrontal cortex. And it turns out that run-of-the-mill depression looks a good deal like these "medical depressions." In autopsies of depressed patients, the brains show subtle disorganization in the prefrontal cortex.
No one expects the cause of depression to be located in one cortex of the brain. Psychiatric research is turning up anatomical differences in diverse regions that regulate emotion. Nor, despite the mixed showing in the JAMA study, has psychotherapy lost its role in treatment for depression.
But evidence from a number of quarters is making depression appear more "medical" — the result and cause of concrete pathology in discrete parts of the brain and then throughout the body. The JAMA study finding that depression is treated inadequately suggests that family doctors have yet to adopt this view. The cardiac research hints that they may have to — in which case, the cultural standing of depression may change as well. Depression may look ever less like a charming element in the artistic temperament and ever more like a progressive, systemic disease.
Peter D. Kramer, the author of "Listening to Prozac," is working on a new book about depression.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
The Interaction of Depression and Medical Illness
DisclosuresJohn J. Spollen III, MD David Gutman, BS
Depression and Comorbid Cardiovascular Disease
It is important to understand the interplay of medical and psychiatric disorders. Charles B. Nemeroff, MD, PhD, Reunette W. Harris Professor and Chairman, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, offered a review of the relationships between cardiovascular disease and depressive disorders at this year's American Psychiatric Association annual meeting.[1]Several large studies have now demonstrated a relationship between depression and ischemic heart disease (IHD). A study by Anda and colleagues[2] followed more than 2800 participants for a mean of 12.4 years and demonstrated that patients with depressed affect and/or moderate/severe hopelessness, as assessed by a general well-being schedule given during their initial baseline assessment, had a much higher risk for both fatal and nonfatal IHD. This study clearly suggested that depressive-like symptomatology may be a risk factor for the subsequent development of IHD. Depression is also very common in patients with coronary artery disease (CAD). Approximately 23% of patients met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for depression in a study by Gonzalez and colleagues.[3] In this study, both family history of psychopathology and the severity of medical illness were significant predictions of depression.
In another study, patients who met DSM-III-R criteria for depression 7 days after a myocardial infarction (MI) were also assessed both 6 months and 18 months after an acute MI. The rate of coronary deaths among the nondepressed patients (n = 187) was approximately 3% at 6 months and 6% at 18 months. Among the depressed patients (n = 35), the incidence of coronary death was approximately 16.5% at 6 months and 20% at 18 months, demonstrating that depression particularly increased the rate of coronary death within 6 months of the initial MI.[4,5] The results from the Baltimore ECA follow-up study also determined the role of major depression as a risk factor for MI and factored in the involvement of psychotropic medications. This study demonstrated that depression increased the risk of developing an MI by 4.54, and even dysphoria increased the odds ratio for developing an MI by over 2-fold. This study also demonstrated barbiturates, phenothiazines, and lithium were associated with an increased MI risk. whereas tricyclic antidepressants (TCAs) were not.[6] A number of large prospective studies in patients without CAD upon study entry have now demonstrated that depression is a significant independent risk factor for CAD, with an adjusted relative risk in the range of 1.5- to 2-fold, which is similar to tobacco and smoking.
There are several possible mechanisms that may underlie the increased propensity for IHD in patients with depression. Depression is associated with a number of alterations, including hyperactivity of the hypothalamic-pituitary (HPA) axis and increased sympathetic activity. There is also evidence suggesting elevated secretion of cytokines, which are powerful mediators of the immune system. Functional abnormalities in platelet function have received particular attention, as they are one of the key mediators of clot formation. It is also notable that platelets have neuroectodermal origin and so are of the same lineage as central serotonergic neurons.
A small study by Musselman and colleagues,[7] which measured a number of markers related to platelet activation, showed exaggerated platelet reactivity in patients with major depression. A study by Pollock and colleagues[8] also demonstrated increased platelet activation in patients with IHD and depression. Of particular interest, treatment with paroxetine (a selective serotonin reuptake inhibitor [SSRI]) but not nortriptyline (primarily a norepinephrine reuptake inhibitor) reduced measures of platelet reactivity in this study. Agents that target serotonin may be particularly effective, as serotonin is directly involved in platelet activation and has antiplatelet activity, which may be demonstrated by the frequent occurrence of bruises in patients taking SSRIs. Several studies have also demonstrated SSRIs are effective in reducing platelet activation in depressed patients.[9,10]
Independent of increased platelet reactivity, depression has also been associated with reduced heart rate variability, a known predictor for poor outcome in CAD.[11] Dr. Nemeroff highlighted the fact that tricyclic drugs are particularly dangerous in patients with heart disease, as they reduce heart rate variability. Reductions in heart rate variability may result in heart failure, conduction abnormalities or arrhythmia in the diseased heart (although they may produce only orthostatic hypotension in a healthy heart).
A large study was undertaken (the SADHART trial) to evaluate the cardiovascular safety, tolerability, and antidepressant efficacy of sertraline treatment in patients with an acute MI or unstable angina. Overall, this study demonstrated sertraline to be safe and effective in this population. Although sertraline did not significantly lower the development of adverse cardiovascular events relative to placebo, most measures showed improvements in the sertraline group.[12] It is likely that this study was underpowered; of the more than 11,500 patients interviewed, only 369 patients successfully completed the study. Overall, some compelling evidence was presented suggesting depression is an independent risk factor for the development of IHD, and that SSRIs may be particularly effective in reducing the incidence of adverse cardiovascular events in these patients.
Medical Illness and Depression
Concerning the effects of depression on other major medical illnesses, Dr. Musselman reviewed some of the recent literature outlining how depression can influence the treatment of diabetes, stroke, and cancer.[13] Current data indicate that the lifetime prevalence of depression in the general population may range from 2% to 15%, while it is much higher in patients with diabetes (9% to 27%), stroke (22% to 50%), or cancer (18% to 39%). Thus it is important to understand how depression may influence the treatment and long-term outcome of disease in these patients.[14,15]Several studies have now demonstrated that there is at least a 2-fold increased risk for developing depression in diabetic patients (type 1 or type 2); and among children and adolescents with type 1 diabetes. there is at least a 2- to 3-fold increase in the prevalence of depression. Women, minorities, and patients with lower socioeconomic status or physical disability are particularly at risk.[16,17] Diagnosing depression in this population can also be difficult in that some of the key symptoms of both diseases overlap, including insomnia, fatigue, and changes in appetite. Fortunately, exclusive diagnostic criteria that eliminate somatic symptoms can be successfully employed in diabetes patients to discriminate depressed vs nondepressed patients.[18]
Comorbid depression is known to increase the incidence of diabetic complications and is associated with poor adherence to diabetic medication, exercise, and diet, as well as poor glycemic control.[19,20] Depression itself is also often associated with elevated glucocorticoids, which may further complicate diabetes. One study actually showed elevated glucose levels and insulin resistance in depressed patients following an oral glucose tolerance test.[21,22] Indeed, depression may increase the risk for subsequently developing diabetes by nearly 2-fold.[23]
It is clear that depression may further complicate diabetes, and it is important to ensure that the medications used to treat depression do not further worsen the condition. Monoamine oxidase inhibitors and TCAs in combination with sulfonylureas may induce hypoglycemia, and TCAs and mirtazapine may increase weight gain and HbA1c levels. However, SSRIs may be useful treatments in such patients. Fluoxetine, and presumably SSRIs in general, have been shown to produce an increase in insulin sensitivity, and sertraline has been shown to actually lower HbA1c levels. TCAs and SSRIs are also useful treatments for painful neuropathy, which is common in diabetics.[24,25] The importance of treating depression in diabetic patients has also been shown, as treatment is associated with better quality of life and improved glycemic control.[19]
Depression is also very common in stroke patients (approximately 15% to 25%) and is particularly common in females.[26,27] One of the key questions is whether the stroke itself may directly affect the circuits involved in depression. A recent meta-analysis did not demonstrate that the location of stroke affected the incidence of poststroke depression ,[28] although it is possible that specific left-frontal cortical strokes may specifically increase the rate of depression.
Not surprisingly, poststroke depression is associated with a lack of recovery in daily activities.[29] It is also associated with a reduced 10-year survival. In one study, approximately 60% of nondepressed patients were still alive 10 years after their initial stroke, compared to only about 30% of depressed patients.[30] A 6-week study with citalopram demonstrated it was a safe and effective treatment in poststroke depression.[31] A 52-week, double blind, randomized trial demonstrated sertraline significantly decreased the incidence of depression (all patients were not depressed when enrolled in the study) and was also associated with a decrease in adverse events. The rate of cardiovascular disease was particularly reduced in sertraline-treated patients, most likely due to the antiplatelet/anticlotting effects of SSRIs.
Depression is also very prevalent in cancer, with rates in some forms of cancer (pancreatic, oropharanygeal) as high as 40% to 50%.[32] Chronic depression may also be a risk factor for developing cancer.[32] The field of psychoneuroimmunology is particularly intriguing, and suggests possible mechanisms where the immune system and nervous system interact. One of the best demonstrations of the powerful interaction between these two systems is that immune activations resemble many of the cardinal symptoms (ie, "sickness behavior"). Cytokines, which are powerful modulators of the immune system and released after infection, can produce anhedonia, malaise, weakness, social withdrawal, anorexia, hypersomnia, and hyperalgesia, which are all reminiscent of the major symptoms in depression. Patients with major depression also have elevated serum concentrations of interleukin (IL)-6, a powerful proinflammatory cytokine.[33]
Cytokines, particularly interferons, have also been used to treat a number of medical conditions, including severe viral infections (hepatitis) and certain cancers (particularly malignant melanoma). Although effective treatments, the use of interferons has been associated with a number of debilitating side effects including flu-like symptoms, fatigue, nausea, anorexia, vomiting, and, in some cases, mood changes, cognitive changes, and/or psychosis.[34-36] As depressive symptoms are particularly common following long-term interferon treatment, Dr. Musselman's group recently completed a study where they prophylactically treated nondepressed melanoma patients for 2 weeks with paroxetine (20-40 mg/day) prior to initiation of interferon treatment. After 12 weeks of interferon-alpha treatment, the rate of depression was approximately 50% in the placebo group, vs about 10% in the paroxetine group.[37] Paroxetine was also associated with significantly higher compliance (fewer patients had to discontinue interferon-alpha treatment).
In conclusion, it is clear that depression hinders compliance, increases symptom burden, and also diminishes survival in both cancer and stroke. Chronic depression may also be an independent risk factor for diabetes and stroke. Although more work is needed, the existing evidence also suggests depression may exacerbate diabetes, stroke, and cancer. Dr. Musselman concluded by suggesting that prophylactic antidepressant administration may be reasonable in medical patients at high risk for depression.
poster:jrbecker
thread:238122
URL: http://www.dr-bob.org/babble/20030624/msgs/238122.html