Monday, May 3, 2004
Brain Stimulation: New Treatments for Mood Disorders Chair: A. John Rush, MD Professor, Department of Psychiatry, University of Texas, Southwestern Medical Center ECT: Role in Brain Stimulation Harold A. Sackeim, PhD Department of Biological Psychiatry, New York State Psychiatric Institute Department of Psychiatry and Radiology, Columbia University In introducing this symposium, Dr. Rush stated that current treatments for depression fall short of expectations. To this point, Dr. Sackeim added, “present treatments are just a few steps beyond blood letting,” especially considering side effects and limited efficacy. Electroconvulsive therapy (ECT), at 70 years old, is the oldest somatic treatment in psychiatry. Magnetic stimulation therapy is thought to be a better option. Dr. Sackeim discussed treatment progress, remarking that progress is not linear or step by step, but occurs in spurts. According to him, “side effects seen in today’s treatments occur because the drug or treatment is in a place we don’t want it to be.” Ultimately, it is the therapeutic effect, not which technique is better, that is important. Dr. Sackeim reviewed the results of a study of ECT treatment techniques at 7 New York hospitals: despite variations in ECT methods, there was no difference in efficacy across the hospitals in the study. In recent years, improvement of ECT has been investigated because simply inducing seizures is not sufficient to treat depression. Research has indicated that the site where electrodes are placed on the head may influence treatment. There was greater retrograde amnesia with bilateral ECT. ECT shuts down prefrontal cortex blood flow, and this change predicts response—people displaying this change responded well (95% accuracy). Recent research has also revealed that the electrical pulse introduced to the scalp of an ECT patient has been greater than needed. Another modification of ECT described was ultra-brief stimulation. This method has been demonstrated to speed recovery, and its use is considered more important than whether the patient receives bilateral or right unilateral stimulation. The use of ultra-brief stimulation results in marked savings on cognitive measures. This new method extends the range of devices (greater efficiency) since a lower voltage is needed. Right unilateral ultra-brief stimulation appears to be optimal. Dr. Sackeim also briefly described FEAST, a method using a special electrode area with an anode and cathode, which allows much sharper focusing of current density. The goal of this technique is to produce unilateral right frontal seizures. It involves less current used more intensely on the focal area, as opposed to more current diffused over a large area. Repeated Prefrontal Repetitive Transcranial Magnetic Stimulation as an Antidepressant: An Update Ziad Nahas, MD Assistant Professor, Medical University of South Carolina Although transcranial magnetic stimulation (TMS) is not yet approved for the treatment of depression, it has some promise. It is based on the notion that inducing a seizure may not always be necessary. With TMS, a magnetic field to depolarize neurons in the brain is created. This magnetic field is a short pulse that produces a magnetic field equivalent to 20,000 times the earth’s gravitation. This intense magnetic field can penetrate tissue. The sites of TMS activation run parallel to the scalp. Under MRI imaging, TMS-induced brain activity is similar to that seen in normal physiology. Although its clinical application is still being determined, its antidepressant properties have been studied for 10 years. TMS stimulates the frontal cortex and so far appears safe. It doesn’t cause shrinkage of the brain, and no patients have suffered long-term side effects. As with ECT, location of the stimulus site is important. More pulses per day have been shown to have a greater influence on outcome. TMS treats depression by rebalancing the relationship between the cortex and limbic regions of the brain and affecting the HPA circuitry. Thus far, more than 30 animal studies of TMS have been conducted. One human study in patients with DSM-IV–defined major depressive disorder is under way. Dr. Nahas concluded his talk by stating that remission, not response, should be the key word; a 50% response in a severely depressed patient still leaves the patient with depression. Magnetic Seizure Therapy: Development of a Novel Convulsive Treatment Sarah H. Lisanby, MD Director, Magnetic Brain Stimulation Lab, Columbia University/NY State Psychiatric Institute Dr. Lisanby discussed the use of magnetic seizure therapy (MST), which differs from TMS in that patients are placed under anesthesia. This method is used to trigger a focal cortical seizure. It was developed because of the side effects observed in patients on ECT and because some patients refuse ECT, and because ECT’s efficacy is not complete. The goal of this MST is to target the prefrontal cortex, thus maximizing efficacy, sparing the temporal cortex, and minimizing side effects. This type of magnetic treatment has the advantage of being able to penetrate into the brain unimpeded, up to about 2 cm. It also offers better control over induced electrical seizures and uses less current per pulse than ECT. The first animal studies, with the rhesus monkey, were done in 1998; the first human trials were conducted in 2000. With this procedure, there is prefrontal cortex stimulation that does not spread to the hippocampus. There has been no evidence of neurophysiological damage with MST. There is also less synaptic remodeling and mossy fiber spreading with this procedure compared with ECT. It is thought that the formation of mossy fiber spreading can affect cognition. In a clinical trials comparing MST with ECT, fewer side effects (muscle aches, memory loss, and headaches) were seen in patients receiving MST. Cognition was better with MST, with less retrograde amnesia in patients receiving MST. Dr. Lisanby concluded her presentation by stating that the evidence for antidepressant effects for MST is there, but that controlled trials are still lacking. The Use of Vagus Nerve Stimulation (VNS) in the Long-term Treatment of Mood Disorders Laurent B. Marangell, MD University of Texas Dr. Marangell started
her presentation on vagus nerve stimulation
(VNS) by indicating that this technique will likely be used in
conjunction with other treatments for depression. Currently, it
is approved in Europe and The vagus nerve is a major pathway to the brain via the afferent nerve. Epilepsy patients, for whom VNS is currently approved, noted improved quality of life. Over the long term, the response rate increases, up to 43% 2-3 years after implantation. Side effects also decrease over time. Dr. Marangell discussed the D-01 study of vagus nerve stimulation for depression. This was an open-label, 12-week study (Rush AJ, et al. Biol Psychiatry. 2000;47:276-286) of treatment nonresponders. Two-thirds had been treated with ECT, and on average, each patient had failed about 4.8 antidepressant treatments. At 12 months, remission rate was about 26%, with QOL improvements seen at up to 2 years. Dr. Marangell then discussed the D-02 study, which mirrored the design of the D-01 study, except that patients who had failed many prior treatments were excluded. Acute response rates were about 15%, versus 10% for those on sham treatment (control). Long term, response and remission rates increased to 29.8% and 17.1%, respectively, over 12 months. Another study, D-04, was conducted to compare patients receiving usual care (antidepressants with no VNS) with patients receiving VNS (D-02 study patients). The patients in the D-02 VNS group achieved better response. The demographics of patients in both studies were similar. This comparison of VNS- and non-VNS patients suggests that changes over time in the VNS group were not related to the antidepressants treatments patients were taking while on VNS. As noted by Dr. Marangell, there are contraindications for VNS: patients should not receive whole-body MRI scans with VNS, and VNS has not been studied in patients with recent cardiac problems. She suggested that the response to VNS may continue over time, unlike response to drugs, which may diminish over time. Dr. Rush offered support of VNS therapy by stating, “patients don’t ask to have VNS stopped, but [they do] ask for medications to be reduced.” Plotting a Course to Remission: Navigating the Intersection of Mind, Brain, and Body Supported by Eli Lilly and Company and Boehringer Ingelheim Pharmaceuticals, Inc. Chair: Alan F. Schatzberg, MD Kenneth T. Norris, Jr Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine This symposium focused on the increasing attention paid in recent years to understanding the biological underpinnings of mind-body connections and their implications for treatment and outcome. This symposium presented data on mind-body relationships, particularly in comorbid pain and depression and in special patient populations (eg, the elderly, for whom comorbid medical and psychiatric syndromes are common, and women with depression, for whom estrogen and progesterone play putative roles). Commonly overlooked in practice, these interfaces and comorbidities can play key roles in achieving remission. Does Everybody Hurt? Epidemiology of Physical Symptoms and Depression Maurice M. Ohayon, MD, DSc, PhD Associate Professor, Department of Psychiatry and Behavioral Sciences, Stanford Sleep Epidemiology Research Center Dr. Ohayon presented epidemiological data on pain and depression from 2 studies: one on 18,980 subjects in 5 European countries and the other on 2017 subjects in California. These data were obtained by telephone interviews using the Sleep-EVAL system. In the European study, major depressive disorder (MDD) was observed in 4% of subjects. Physical symptoms, such as insomnia (71.3%), fatigue (52%), weight loss (43.9%), psychomotor retardation (26.7%), psychomotor agitation (24.8%), hypersomnia (19%), and weight gain (15.2%), were frequently reported by MDD patients. Pain, a symptom not included in the DSM-IV classification of MDD, was present in 43.4% of the group with MDD. In the California study, the prevalence of MDD was 7% (5.1% with pain + 1.9% without pain). The most frequent types of chronic pain reported by MDD patients were chronic back pain (43.4%) and chronic neck pain (34.5%). Subjects with MDD were also more likely to have: · Needed bed rest (28.4% vs13.9% of non-MDD patients) in the past year · Consulted with a physician about pain (67.6% vs 55.5% of non-MDD patients) · Needed sick leave for pain and pain medication use Dr. Ohayon concluded his presentation by stating that nearly half of individuals with MDD have a chronic painful physical condition. He also indicated that pain in MDD exacerbates fatigue, insomnia, weight gain, and concentration problems. Comorbidity With Painful Physical Symptoms: Understanding the Intersection of Brain and Body Bruce A. Arnow, PhD Associate Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine Dr. Arnow began with a survey of major depressive disorder (MDD) prevalence rates in primary care from various studies, which range from 7.3% to 10.5%. Additional studies indicate that the prevalence of chronic pain is 46% in general practice and 38% in primary care. Depression and chronic pain frequently coexist, though the magnitude of the relationship is unclear. The recognition of depression in primary care is often complicated by the presentation of somatic complaints, such as pain. Dr. Arnow’s own research demonstrates that 66% of MDD patients have chronic pain. In another study, by Blair MJ, et al (Psychosom Med. 2004;66(1):17-22), 44% of patients with depression had moderate-to-severe pain. Chronic pain and depression impact quality of life, somatic preoccupation, and anxiety disorders. Comorbid MDD and chronic pain led to higher scores on the Health-Related Quality-of-Life scale; higher somatization scores; and high rates of panic and anxiety disorders. Medical costs are higher for patients with both MDD and chronic pain. Child sexual abuse (CSA), another comorbidity with depression, results in more physician visits, abdominal surgeries, hospitalizations, and overall medical costs. Patients with history of CSA and physical abuse along with depression had more emergency room visits than those with depression or CSA alone. Dr. Arnow also briefly discussed the results of the ARTIST study, which examined the effect of chronic pain on antidepressant treatment response. There is some evidence that chronic pain can attenuate the benefits of antidepressant therapy. Serotonin and Norepinephrine: Navigating the Broad Range of Symptoms Pedro L. Delgado, MD Douglas D. Bond Professor of Psychiatry, Chairman,
Department of Psychiatry, Dr. Delgado began his presentation by discussing the recurrent nature of major depressive disorder (MDD). Seventy-five percent to 90% of MDD patients have multiple episodes, and with each new episode, recurrence becomes more likely and more treatment resistant. He also observed that with each subsequent episode of depression, there is less association with life stress as a precipitator. Longer major depressive episodes (MDEs) lead to less complete recoveries. Depression can also cause physical damage, as indicated by studies demonstrating possibly irreversible reduced hippocampal volume in MDD. However, a study by Duman RS, et al (Arch Gen Psychiatry. 1997;54(7):597-606) revealed that antidepressant treatment increased neuronal survival and growth. It is not known how antidepressants help both the physical and emotional symptoms of depression. Neurotransmitter depletion studies indicate neurotransmitters such as norepinephrine and serotonin are involved in MDD, giving support to the dual action of antidepressants such as duloxetine and venlafaxine. Major depression is best characterized as a syndrome of cellular dysfunction in stress-modulating/mood-regulating brain circuits, Dr. Delgado said. Plotting the Course to Remission: Balanced Strategies to Improve Outcomes Vivien K. Burt, MD, PhD Professor of Clinical Psychiatry, The David Geffen School of Medicine at UCLA; Director, Women’s Life Center, UCLA Neuropsychiatric Institute and Hospital Dr. Burt began her presentation by suggesting that current treatments for depression are far from adequate. For example, 2-4 weeks are needed for symptom relief, there is incomplete remission in 20%-30% of initial depression episodes, and the risk of relapse in partial remissions is 50%-80%. These issues have led to a search for more effective treatment. A meta-analysis of 25 studies (Anderson IM. Depress Anxiety. 1998;7[suppl]:11-17) demonstrated that tricyclic antidepressants (TCAs) were more effective than selective serotonin reuptake inhibitors (SSRIs). It was further shown that the TCAs with serotonin and norepinephrine reuptake inhibition were the ones that outperformed the SSRIs. Another study (Nelson JC, et al. Biol Psychiatry. 2004;55(3):296-300) demonstrated that the TCA desipramine combined with the SSRI fluoxetine demonstrated higher remission rates than either drug alone. This has led to the development of a new class of antidepressants called norepinephrine-serotonin reuptake inhibitors (dual reuptake inhibitors), such as venlafaxine and the soon-to-be approved duloxetine. Studies with both of these drugs demonstrate increased remission rates and lower scores on the Hamilton Depression Rating Scales. Dr. Burt then discussed psychotherapy as an augment to treatment. Unfortunately, there are only 2 randomized trials, both small, that test psychotherapy’s role in treatment enhancement. In one study, a combination of pharmacotherapy and short-term psychotherapy was significantly more efficacious than either treatment alone. A recent study by Nemeroff CB, et al. (Proc Natl Acad Sci. 2003;100(24):14293-14296) demonstrated greater improvement in Hamilton Depression scores with combined antidepressant/psychotherapy treatment than with either alone. However, more randomized, placebo-controlled, blinded studies are needed to confirm the role of psychotherapy as an enhancement to pharmacotherapy. Looking Beyond the Symptoms of Depression: Considerations for Special Populations Ruta M. Nonacs, MD, PhD Clinical Instructor, Department of Psychiatry, Harvard Medical School Dr. Nonacs presentation focused on particular populations of depressed patients, such as the women and the elderly. A growing body of research has highlighted a variety of ways in which men and women differ in their responses to antidepressant medications. For example, the lifetime prevalence of mood disorders (major depressive disorder, dysthymias, seasonal affective disorder, and bipolar disorder) differs by gender, with women demonstrating increased rates. Symptom presentation also differs by sex. For example, men have more actual suicides, while women have more suicide attempts. Women have more anxiety and somatic symptoms then men. Treatment response to antidepressants differs by sex as well. Tricyclic antidepressants (TCAs) are more effective in men, while monoamine oxidase inhibitors (MAOIs) are more effective in women. Women respond better to SSRIs. Hormonal status also has an effect on treatment response. Younger, premenopausal women have better success with SSRIs and MAOIs than with TCAs. Older, postmenopausal women do better on TCAs than on SSRIs. Postmenopausal women may have poorer response to antidepressants in general. Based on these observations, it has been suggested that estrogen may enhance antidepressant response. In postmenopausal women treated with sertraline, estrogen replacement therapy (ERT) improved response and remission (Schneider LS, et al. Am J Geriatr Psych. 2001;9(4):393-399). Due to some failed studies, it is still not certain if ERT improves response in women on SSRIs. However, estrogen alone acts as an antidepressant and may enhance serotonergic activity and resolve vasomotor symptoms as well as stabilize fluctuating estrogen levels. In the elderly, considerations such as reduced metabolism, medical comorbidity, cognitive dysfunction, and prevalence of somatic symptoms should be addressed when using antidepressants. A recent study suggests that efficacy with TCAs or SSRIs is similar, with SSRIs better tolerated. Adverse events with SSRIs in the elderly are drug-drug interactions and gastrointestinal bleeding. In the elderly, there seems to be a more rapid onset of action with mirtazapine compared with SSRIs. With the dual-acting agent venlafaxine, remission was greater than with SSRIs, especially in patients aged over 65 years. In looking at side effects with duloxetine in the elderly, there was no significant increase in blood pressure, as has been seen with venlafaxine. In these special patient populations, the goal remains the same, achieving complete remission. Settling for a response may increase the likelihood of relapse or treatment resistance, increase the risk to women’s families, and increase morbidity/mortality in the elderly.
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