Tuesday, May 4, 2004
Clinical Report Session: Issues in Depression Chair: Glenn J. Treisman, MD Brain Bioenergetics and Thyroid Hormone Treatment in MDDDan V. Iosifescu, MD Director, Neurophysiological Studies, Depression Clinical and Research Program, Massachusetts General Hospital Dr. Iosifescu’s presentation described a recently completed study of how thyroid hormone affects depressed patients. He began by reviewing what is known about glucose metabolism and its link to depression. Studies with PET imaging scans reveal an abnormality with glucose in depressed patients, and MRI scans also reveal an altered glucose metabolism in vivo. Thus, altered glucose metabolism may predict treatment response. An abnormality in brain energy metabolism has been observed in patients with major depressive disorder (MDD): decreased beta-adenosine triphospate (ATP, the primary source of cellular energy) in MDD patients compared with normal volunteers. Further, studies in skeletal muscles have revealed that thyroid hormone increases cellular energy metabolism. And the long history of thyroid hormone treatment in depression includes well-established studies demonstrating that tricyclic antidepressant (TCA) efficacy increases 2-fold with thyroid hormone augmentation. There are few “negative” studies on thyroid hormone use in depression. In the brain, metabolism is reduced in MDD; thyroid hormone corrects cellular energy metabolism in the brain through normalization of glucose metabolism. In a study of 20 individuals with DSM-IV–defined MDD who were nonresponders to 8 weeks of fluoxetine treatment, thyroid hormone augmentation was initiated. Brain scans were performed before thyroid hormone augmentation and 4 weeks after. A significant increase in alpha-ATP in responders compared with nonresponders was seen. The same was observed for beta-ATP and total ATP. In those subjects who were treatment resistant, beta-ATP levels were identical to baseline levels. Also, phosphocreatine (PCr) was decreased in responders (implying there are elevated levels in depression). What is the clinician to do with these findings? Dr. Iosifescu responded that it is unknown how these findings will work their way into routine clinical practice. There’s little value in treating with thyroid hormone, he said, except in treatment refractory depression. However, thyroid hormone has value as a “booster” or “jump start” for short-term treatment of refractory depression patients on antidepressants until the body can start producing more thyroid hormone on its own. There doesn’t seem to be any benefit in long-term thyroid hormone therapy since the body eventually catches up with thyroid production on its own, he added. Depression Outpatients From Primary Care Versus Specialty Care SettingsBradley N. Gayne, MD Dr. Gayne discussed the results from the Sequenced Treatment Alternative to Relieve Depression (STAR•D) trial, which set out to compare depression in the primary care setting with treatment in the specialized care setting. This is a 7-year study (1999 to 2007); thus far 2026 patients have been recruited. The objectives of this study are: · To describe the best next steps for treatment-resistant individuals · To compare the efficacy of different treatment strategies · To compare side effects and economic costs · To describe long-term benefit of successful strategies All patients were initially treated with a selective serotonin reuptake inhibitor (SSRI), with nonresponders allowed 4 additional subsequent treatments. Early results suggest that depression in the primary care setting: · Is less severe, with a milder course · Is less likely to present with dysphoria · Is less complicated by physical symptoms · Has a median illness length of 14 years Based on the patients enrolled so far, primary care patients are a little older than specialty care patients and more likely to be female. In specialty care, patients tend to be Caucasian (78%) and have a median illness length of 11 years. Within the specialty setting, patients have twice the likelihood of attempting suicide compared with primary care patients (21% vs 12%, respectively); however, no difference in family history of suicide attempts has been seen. Depression severity is the same in the two settings, with no difference in depression rating scales measures. Surprisingly, prevalence of MDD is also similar. Dr. Gayne pointed out that the study design does have limitations, as patients were enrolled in the study by their primary care or specialty physicians. Additionally, only patients with moderate-to-severe depression were included. Limits to the Treatment of Major Depression Dr. Keitner’s provocative presentation was in stark contrast to many of the presentations at this year’s APA conference in that he felt patients are now being overtreated and not being served in the best ways. Despite the commonly accepted practice of pursuing complete remission, he said that for some patients, remission is not possible. By way of example, Dr. Keitner presented the findings of the venlafaxine meta-analysis by Dr. Thase (Thase M. Br J Psychiatry. 2001;178:234-241). Close examination of the study reveals that efficacy of the various treatments (venlafaxine, SSRIs, and placebo) was not impressive, with remission rates reaching no higher than 47%, and not much higher than placebo treatment. According to Dr. Keitner, efficacy studies are not indicative of the real world, but reflect clinical trial objectives. Effectiveness studies would be more realistic. Clinical trial results are questionable, he said, because many patients are excluded for conditions that are not unusual in depressed patients. He cited results from a Rhode Island clinic of 346 patients suffering from depression. Of those patients, only 29 would have been accepted into a clinical trial using common inclusion criteria (Zimmerman M, et al. Am J Psychiatry. 2002;159:469-473). Dr. Keitner’s review of numerous published drug studies also suggested that studies published by authors with financial ties to pharmaceutical companies had a tendency to make that company’s drug look better. Psychotherapy results are also unimpressive, he said. Cognitive behavior therapy (CBT) and behavior therapy achieved response rates of only 50%, and interpersonal therapy (IPT) achieved a response rate of only 52%. Overall, there was little difference in the results of psychotherapy versus pharmacotherapy, except that remission and dropouts were more common with pharmacotherapy. Data supporting the combination of pharmacotherapy and psychotherapy are not robust enough to yield any conclusions, he added. For severely depressed patients, psychotherapy has not been shown to be effective unless combined with pharmacotherapy, family therapy, and cognitive therapy together. In patients for whom pharmacotherapy, psychotherapy, or a combination of the two don’t work, switching from one drug to another within the same drug class helps about 50% of the time, Dr. Keitner said. The use of polypharmacy has steadily increased over the past 2 decades, with percentages of patients receiving polypharmacy increasing from 52% in 1980 and earlier to 69% from 1981 through 1990 and 80% from 1991 through 2000. Though 75% of physicians use a combination regimen of antidepressants with their patients, there is not much information from studies indicating that this improves responses. Augmentation therapy (adding one drug to enhance another drug) is still being evaluated in studies. Looking at electroconvulsive therapy (ECT), Dr. Keitner reported that in a community study of 347 patients, response rate was 63.7%. Defining remission as a HAMD ≤ 10, remission rates were 46.7%. Defining remission as a HAMD ≤ 7, remission rates decreased to 30.3%. Results from repetitive transmagnetic stimulation (rTMS) therapy results are also unimpressive, he said. Dr. Keitner concluded by reiterating that current treatments for depression are not adequate, which can make both the physician and patient feel let down. This is not unique to depression; other illnesses, such as diabetes, have the same problem. Physicians should be honest about treatment expectations, he said, and help patients make the best of their situation if complete remission is not achieved. The goal of complete recovery is unrealistic, in his view. Physicians should let patients know that while there may not be a cure for depression, coping strategies can and should be developed. In Dr. Keitner’s words, “we can’t be hopeless, or else they feel it themselves.” Working with the patient in whom remission is not achieved requires an investment of time on the part of the physician, a difficult dilemma in today’s time-limiting, fee-based reimbursement environment. The reimbursement system should be time based to allow physicians to spend more time with these patients, he said. Behavioral Activation, Cognitive Therapy, and Medication for Major Depression Chair: Steven D. Hollon, PhD, Department of Psychology, Vanderbilt University Methods and Acute-Phase Outcomes Sona A. Dimidijan, MD Dr. Dimidijan’s discussed a modification on cognitive behavioral therapy (CBT), called behavioral activation (BA). Behavioral activation is based on the premise that depression can be brought on by how a person reacts to unfortunate things in life (eg, job loss or death of loved one). A person may withdraw from the things that are necessary for dealing with such unfortunate circumstances. Behavioral activation appears to be a set of coping techniques for enabling the patient to overcome the events or circumstances that are making them unhappy. The elements of BA include: · Focusing on avoidance (avoiding the problem maintains it) · Exposing what the individual is avoiding or withdrawing from · Problem-solving techniques and homework assignments To test the efficacy of BA in acute treatment (8 weeks) of major depressive disorder (MDD), a comparative study of CBT, paroxetine, placebo, and combination treatments of psychotherapy with placebo or paroxetine was conducted. It was thought that BA, cognitive therapy, and paroxetine would have equal efficacy. The study results indicated that the rate of attrition was higher in those patients taking paroxetine (mainly because of side effects). The mean dose of paroxetine was increased throughout the study to 35 mg/day. The results indicate that in moderate to severe depression, BA and paroxetine were more effective than placebo; however, cognitive therapy was no better than placebo. For patients with low-severity depression, there was no difference between the active treatment groups and placebo using the Beck Depression Inventory (BDI) and Hamilton Depression (HAMD) scales. In the high-severity group, BA and paroxetine were equally effective, using the BDI and HAMD scales. Looking at baseline characteristics for potential predictors of treatment response, demographics, history, psychosocial problems, functional impairment, and comorbidities were identified as moderators of treatment outcome. For example, chronicity and unemployment predicted poor response in all treatment arms of the study. Based on this study, BA emerges as a strong and promising acute-phase treatment compared with pharmacotherapy and cognitive therapy. Behavioral activation has greater acceptance by patients and lacks the side effects of pharmacotherapy. Behavioral activation may also have benefit as a component of a combined treatment approach. Prevention of Relapse and Prediction of Treatment Response Keith S. Dobson, PhD Dr. Dobson’s presentation was a follow up to Dr. Dimidjian’s presentation on the acute phase of the behavioral activation validation study. After treatment end in the acute phase, patients in the paroxetine treatment arm had a greater relapse rate (40%) compared with the other active treatment groups; BA and cognitive had lower relapse rates. More specifically, in the second year, 85% of patients responding to paroxetine treatment relapsed after paroxetine treatment ended. From this observation, it was surmised that antidepressant therapy has little lasting effect. The patients on BA or cognitive therapy had sustained benefits over years of follow-up. From a pharmacoeconomic standpoint, psychotherapy is more expensive in the short term than pharmacotherapy; however, over time the cost of pharmacotherapy increases due to its chronic administration. Psychotherapy usually requires only a specific number of sessions compared with the long-term nature of a course of antidepressant pharmacotherapy. In summary, Dr. Dobson said the attributes of BA are that it is effective, enduring, and easy to teach and transport and that it can be integrated into clinical management. During the discussion session, Drs. Dobson, Hollon, and Dimidjian further explained behavioral activation and its distinctness from other forms of psychotherapy. In comparison, cognitive therapy is more rigid, with many ways for the therapist to go wrong. Behavioral activation, on the other hand, has some leeway for the therapist to experiment and modify based on the patient’s situation. Behavioral activation is relatively easy to learn, basically by reading as little as 1 article about BA. However, Drs. Dobson and Hollon indicated that individuals trained psychodynamically may have trouble learning this technique due to the mindset instilled from their training. Psychiatrists, who have been trained in supportive techniques, would be adept at learning BA. In a discussion with Dr. Hollon and Dimidjian, the issue of the length of treatment for BA was introduced. Both Drs. Hollon and Dimidjian indicated the normal course of treatment would be 16 weeks. It is not clear if a shorter duration of BA treatment would be more advantageous. |