Wednesday, May 5, 2004
Treatment-Resistant Depression Chair: Charles B. Nemeroff, MD Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine Introduction to Treatment-Resistant DepressionCharles B. Nemeroff, MD “We need to know when to move from the science of psychopharmacology to the art of psychopharmacology.” This statement from Dr. Nemeroff set the tone for his presentation on the dilemma posed by patients who have proven resistant to antidepression treatment. The majority of depressed patients are treated by nonpsychiatrists, leaving the more difficult to treat cases on the doorstep of the psychiatrist. In the view of Dr. Nemeroff, patients should be encouraged to seek a second opinion, especially if the patient has received little or no response from an antidepressant course of treatment, since a firm diagnosis is crucial to treatment response or remission. Not enough questions are asked during the initial screening for depression, and many diagnostic clues that can point the patient toward the most appropriate treatment are missed, he said. Dr. Nemeroff believes there are 3 factors to consider in treatment-resistant depression (TRD): “diagnosis, diagnosis, and diagnosis.” Concerning factors contributing to TRD, Dr. Nemeroff indicated that the number 1 cause of TRD is hyperthyroidism. Thus TSH testing is urged. Inadequate dosing is also a factor in TRD, since some individuals are fast metabolizers. Slow metabolizers, on the other hand, may be at increased risk for side effects. Success in treating TRD is influenced by: · Correct diagnosis · Comorbid psychiatric conditions · Appropriate drug therapy · Severity of illness · Comorbid medical illness · Adequate dosing · Adequate duration · Compliance Within the population of patients who are treatment resistant, the following subtypes of depression are seen: · Atypical depression · Double depression · Psychotic depression · Severe and melancholic depression · Comorbidity of psychiatric and medical conditions · Psychosocial issues For example, patients with psychotic depression may have an ego structure that prevents them from admitting certain symptoms, withholding information vital for a diagnosis. Early-life trauma is something the physician should inquire about, especially since patients with early-life trauma are more likely to respond to psychotherapy; those without this history are more likely to respond to pharmacotherapy (Nemeroff CB, et al. Proc Natl Acad Sci. 2003;100:14293-14296). Reasons for nonresponse to pharmacotherapy include: · Noncompliance · Underdosing · Delayed response · Poor gastrointestinal absorption · Concurrent drug therapy/medical condition · Incorrect diagnosis · Psychosocial factors · True nonresponse · Alcoholism Echoing the frustrations regarding the limits of today’s treatment for depression expressed in Dr. Keitner’s presentation yesterday, Dr. Nemeroff indicated that remission is not being achieved by as many patients as hoped. Roughly 50% of patients fail to achieve remission. The FDA defines a 50% reduction in the MADRS or Hamilton depression rating scales as insufficient. Physicians should strive for sustained remission (recovery), Dr. Nemeroff said. HAMD Scale for Depression.
HAMD ≤7 = Remission According to Dr. Nemeroff, physicians should not limit themselves to monotherapy for depression. Triple-drug therapy is standard in medicine for other illnesses. If additional drugs are necessary, they should be added if they offer improvement. To evaluate remission in the clinical practice, physicians should look at how the patient is functioning in the home, work, or family environment. Not achieving remission leads to: · Increased risk for relapse · Increased difficulty achieving remission · Increased suicide risk · Substance abuse Achieving remission leads to low levels of comorbidity, decreased chances for relapse, better social adjustments/functioning, and lower health costs. Depression is a risk factor for coronary artery disease and worsens poststroke morbidity. Chronicity is another factor predicting outcome. Depressive episodes of a longer duration lead to less complete recovery. When choosing which treatment to use, one needs to look through published studies for comparative date and decipher misleading studies, Dr. Nemeroff added. One should consider the sample size, whether the trial is placebo controlled or not, whether it is open label or double blind, whether the dosing is fair and realistic, and the magnitude of the placebo response. To illustrate the confusion that arises from clinical drug studies, Dr Nemeroff examined the results of a meta-analysis (Thase ME, et al. Br J Psychiatry. 2001;178:234-241) comparing the dual-reuptake inhibitor venlafaxine with various selective serotonin reuptake inhibitors (SSRIs). Initial analysis indicated that venlafaxine was superior in efficacy to SSRIs. However, further analysis by Dr. Nemeroff revealed that venlafaxine and SSRIs are not very different from each other in terms of achieving remission (41% vs 36%, respectively). Since 50% of the time remission cannot be achieved, other therapeutic options should be explored. These include: · Repetitive transcranial magnetic stimulation (rTMS) · Vagus nerve stimulation (VNS) · Psychotherapy · Electroconvulsive therapy (ECT) Long-Term Outcomes in Treatment-Resistant Depression A. John Rush, MD Professor, Department of Psychiatry, University of Texas, Southwestern Medical Center Dr. Rush began his presentation with some statistics indicating that 5 of the top 10 illnesses in the world are mental disorders. People with active medical conditions have a higher prevalence of major depressive disorder (MDD). He defined 2 types of treatment resistance: inability to achieve remission and inability to sustain remission. He presented a staging process for antidepressant resistance: • Stage 1: Failure of adequate trial of 1 class of antidepressant (AD) • Stage 2: Failure of adequate trials of 2 classes of ADs • Stage 3: Failure of adequate trials of 3 classes of ADs, including a TCA • Stage 4: Stage 3 plus failure of adequate MAOI trial • Stage 5: Stage 4 plus failure of adequate ECT course Symptomatic breakthroughs in patients on antidepressant treatments are common. Relapse rates in studies are averaging about 40%, in part due to noncompliance. These results are not encouraging for the patient or the physician. Studies indicate that in patients who respond to AD therapy, 40% move to remission in the continuation phase of a depressive illness, indicating that time duration of treatment plays a role: Results may take time. However, out of those responding during the acute phase, 20% to 33% relapsed. The use of a treatment algorithm to guide the physician achieved better results than standard treatment. The use of an algorithm involved frequent visits, phone follow-up calls, and a treatment coordinator. One-year follow up revealed that the response rate was about 26%, with remissions at 10%. Thus, we still have a long way to go. Dr. Rush turned his attention to vagus nerve stimulation (VNS) as a potential new therapy in the armamentarium of antidepressants. He discussed the basics of the D-04 Trial, which was unusual in design and concept. This was a pharmacoeconomic trial that studied 127 patients who had no response to 2 to 6 treatments. Average age was 46; 69% were female, 88% were Caucasian, 87% had unipolar depression, and 50% had prior hospitalizations. These patients did not receive VNS therapy; the purpose was to measure the course of these patients over time with treatment as usual, to provide an indirect comparison with similar patients treated with VNS in another study (D-02). At the 1-year point, the response rate was 12% to 13%; there was basically no change in outcome. The implications are that we need to develop methods to stage treatment resistance, define when the next steps are not working, and develop long-term treatments. Introduction to a Treatment-Resistant Depressions Patient Registry Martin B. Keller, MD Mary B. Zucker Professor and Chairman, Department of Psychiatry and Human Behavior, Brown University Dr. Keller began with a discussion of the upcoming Treatment-Resistant Depression Patient Registry. This registry was designed to address our lack of knowledge of the course of treatment-resistant depression. The registry will follow a cohort of patients on VNS therapy compared with a cohort of patients without VNS therapy. VNS involves surgical implantation of a device: mild electrical pulses are applied to the left vagus nerve in the neck, and an electrical current stimulates the nervous system. Since the device is surgically implanted, compliance is 100%. To avoid side effects, the stimulation can be increased or decreased with an external magnetic wand. VNS was originally developed for the treatment of epilepsy, for which it is currently indicated by the FDA. Epilepsy patients with depression experienced improvement in their depression. Patients achieved sustained remission up to 1 year, with no drug interactions. The objectives of the Treatment-Resistant Depression Patient Registry are: · To determine the outcome, course, functioning, and treatment received by patients with TRD · Create the first prospective longitudinal study of patients with TRD · Produce data on a population that complements the NIMH collaborative study · Enroll about 9000 individuals The aims of the registry are to examine patterns, course, predictors, and psychosocial outcomes, mortality/morbidity and suicide in TRD; treatment as a mediating variable of outcome; the pattern and course of subsyndromal affective symptoms. Safety and side-effect data will also be collected. Patients will be referred by physicians and there will be with few exclusion criteria, except schizophrenia or enrollment in another clinical trial. For reliability purposes, follow-up will be conducted by phone interviews by a central group. The registry is expected to collect long-term efficacy, safety, quality of life, health-care utilization, and psychosocial information. Long-Term Treatment and Outcomes in Treatment-Resistant Depression With Pharmacotherapy, ECT, Repetitive Transcranial Magnetic Stimulation, MST, and VNS Therapy Thomas E. Schlaepfer, MD University of Bonn and The John Hopkins University Despite advances in treatments for depression, only 51% of patients respond to therapy, and 34% do not. Thus, only 15% remit. Decision-tree algorithms, as discussed in Dr. Rush’s talk, do improve patient response. The last step in the algorithm is ECT, which accounts for only 0.47% of the 21 million cases of depression treated. What next? According to Dr. Schlaepfer, there is brain stimulation, of which there are 5 techniques: • ECT • Repetitive transcranial magnetic stimulation (rTMS) • Magnetic seizure therapy (MST) • Vagus nerve stimulation (VNS) • Deep brain stimulation (DBS) Therapy with ECT combined with antidepressants revealed better response . rTMS involves the use of a magnetic field to induce stimulation in the brain to influence brain neurochemistry. Blood flow increases have been observed in the site of stimulation, thus there is a potential antidepressant effect. However, the clinical significance has yet to be established (Gershon AA, et al. Am J Psychiatry. 2003;160:835-845). The longer the stimulation, the better the response. Distance from the magnetic coil to the brain has a direct relationship to effect since distance reduces the magnetic field—the closer the coil, the better. Dr. Schlaepfer also discussed MST, which is used under anesthesia to induce seizures. The site of stimulation on the brain is more localized than ECT. In 2003, the first human trial was performed, with no cognitive side effects seen. Dr. Schlaepfer then discussed VNS therapy and the 4 studies completed or still under way (D-01, D-02, D-03, D-04). In the first 2 studies (US studies), the response rates in treatment-resistant depression with VNS were 31% and 15%, respectively. The D-04 study, as discussed in Dr. Rush’s talk, didn’t study VNS, just treatment as usual. The D-03 study has recently obtained preliminary results, which Dr. Schlaepfer revealed to the audience for the first time. In this study of 37 patients, response at 3 months was 42%, and at 12 months it was 76%. Dr. Schlaepfer was queried about remission rates. His response was that 27% of patients remitted at 3 months and 37% at 1 year. However, he cautioned that these results were very preliminary. Dr. Schlaepfer summarized the treatment options available and their status.
He also reviewed the issue of depression’s neurotoxic effects on the brain. In studies, hippocampal volume shrinks in long-term depression. Studies indicate that fluoxetine combined with ECT induces neurogenesis (neuron growth). Long-term depression alters the brain’s structure and functionality. Panel Discussion After the formal lecture, the speakers entertained questions from the audience. Q: What are your favorite strategies for treatment augmentation? A: Dr. Nemeroff indicated that he prefers mirtazapine + SSRI or respiradone + SSRI. He also uses lithium. Dr. Nemeroff also offered a case of a patient he treated who had been depressed for 28 years and nonresponsive. He started her on VNS as augmentation and she is now almost in remission. Q: What do you do about nonresponders? A: According to Dr. Nemeroff, almost everyone gets some improvement. A: Dr. Rush indicated “we have to reset our expectations” about depression. Sometimes keeping them alive is a service to them. “By being systematic, we can do better with what we have.” There are no great treatments in the arena, he said. Q: What is the estimate for ECT working? A: According to Dr. Schlaepfer, it is about 50%; however Dr. Keller indicated it was 30% in his experience. Dr. Rush mentioned that there are numerous differences in the way ECT is administered. Q: Does ECT help people respond to previously failed therapies? A: Drs. Keller and Nemeroff felt it was possible, but that the initial diagnosis or administration of the prior therapy may have been flawed. Q: Are other mechanisms for depression treatment being explored? A: Dr. Nemeroff indicated that corticotropin-releasing factor (CRF) antagonists and an MAOI patch are being explored to exploit the vast number of neurotransmitters in the brain. |