Sunday, May 2, 2004
Antidepressant Treatments You May Not Know About…But
Should Chair: Jerrold R. Rosenbaum, MD To rely on currently available medications is to be limited to 50-year-old technology, employing mechanisms of action essentially comparable to the original tricyclic antidepressants. Although these agents are superior to placebo and although newer agents have tolerability and safety advantages over older ones, the proportion of depressed patients treated who remit and recover from depression in a sustained way is a small minority of those treated. The search for alternatives and the effort to improve on efficacy is a compelling and ongoing mission for the field of psychiatry. This symposium reviewed the broad array of technologies for the treatment of depression with a concentrated focus on those in development, soon to be available, or less well known to the practitioner. It was chaired by Dr. Jerrold R. Rosenbaum, MD, chief of psychiatry at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School. The Next Generation of Antidepressants Jonathan E. Alpert, MD, PhD, Associate Director of Depression Clinical Response Program, Massachusetts General Hospital Dr. Alpert began his presentation with the idea that there have been a number of new antidepressants, but that there hasn’t been much change in the mechanism of action of these drugs, with a lot of room left for improvement. For example, nausea is the leading cause of patient discontinuations. Other issues include slow onset, inadequate response, GI effects, weight changes, sexual dysfunction, compliance, etc. To help address these issues, new mechanisms of action are being explored. These include: · Serotonin-norepinephrine reuptake inhibitors · Norepinephrine-dopamine-serotonin reuptake inhibitors · Serotonin-1A agonists (5HT1A) · Glucocorticoid antagonists · CRF antagonists · Substance P · MAO-B inhibitors 5HT1A agonists, developed in the mid 1980s, have potential in depression efficacy, based on clinical trials. PET studies have indicated that depression is associated with reduced 5HT1A receptor binding in cortical regions of the brain. Currently, buspirone is the only 5HT1A approved by the FDA, and is approved for anxiety only. Studies of the 5HT1A agonist gepirone have demonstrated increased remission and relapse rates compared with placebo, with little or no weight gain; however, comparative data with SSRIs is lacking and the rate of dizziness appears to be higher than with SSRIs, though it is still well tolerated. FDA approval is expected in about 1-2 years. Dr. Alpert then discussed the glucocorticoid receptor antagonist RU-486. RU-486 is actually referred to as the “morning-after” pill and is approved for elective pregnancy abortion; it is a progesterone antagonist. However, at higher doses it blocks glucocorticoid receptors, thus blocking the toxic actions of cortisol. Glucocorticoid receptor antagonists have potential in psychotic major depression, a difficult to treat disorder, and may provide an “initial boost” for patients with psychotic depression before follow-up with an antidepressant. Again, more evidence from well-controlled studies in the acute and maintenance phases of depression is needed. Another novel therapy discussed by Dr. Alpert was substance P receptor antagonists, discovered in the 1930s. The receptor binding sites (NK1) for substance P antagonists are located near binding sites for monoamine neurotransmitters. It has been observed that antidepressants reduce levels of substance P in several brain regions. In a model of stress, the addition of substance P antagonist to fluoxetine enhanced efficacy, thus it may provide an additive or synergistic effect with antidepressants. Currently, several trials have indicated a broad efficacy across the severity spectrum of depression, though more studies are needed in light of some failed studies. It is generally well tolerated with few GI effects, little/no sexual dysfunction, and long-term compliance. Corticoid receptor hormone (CRH) is implicated in depression based on decreases in CRH in spinal fluids of depressed patients experiencing recovery. Persistent CRF reduction in cerebrospinal fluid is associated with stable remission over time. Post mortem studies demonstrate increased CRH levels in the hypothalamus of depressed patients. Though still in the early stages, this will be an exciting area of development. Alternative Medications for Development Andrew A. Nierenberg, MD, Associate Director of Depression Clinical and Research Program and Medical Director of the Bipolar Programs, Massachusetts General Hospital Alternative medications are used
by millions of people for the treatment of depression. Dr. Nierenberg’s
talk focused on 3 alternative medications: St. John’s wort, folate and SAMe, and omega-3 fatty acids. The
evidence for efficacy and safety of these is far from established
and generally viewed with skepticism by traditional researchers.
Dr. Nierenberg provided an origin for the name St John’s wort. It is harvested on about St.
John the Baptist day (June 24th) and has a red color when ground up, as in the blood
of St. John. Widely used in Europe, its mechanism of action is unknown and has weak serotonin
activity. Within the past few years, rigorous clinical trial methodology
has been used to assess the usefulness (or lack thereof) of these
widely available natural products. Two Dr. Nierenberg’s discussion continued with folate, which is a chemical the human body does not produce, but needs. Today, folate is found in flour, thus most of us get enough of it in our diets. Low levels of folate have been associated with depressive symptoms, apathy, fatigue, insomnia, irritability, and impaired concentration. S-adenosyl methionine (SAMe), a dietary supplement, is needed by the body for synthesis of the neurotransmitters, norepinephrine, dopamine, and serotonin and other intracellular pathways. Placebo-controlled studies indicate some efficacy of SAMe over placebo, though more research is needed to establish it as a potential natural antidepressant. Omega-3 fatty acids are a subset of polyunsaturated fatty acids needed for the maintenance of multiple systems and processes such as neurotransmission, inflammation, and cell excitability. Its potential in depression efficacy as mono- or adjunct therapy has yet to be proven. Dr. Nierenberg concluded by stating that “none of these above therapies has sufficient evidence to get approval from the FDA.” Evidence-Based Psychotherapy for Depression: Principles and Practice Timothy J. Petersen, PhD, Depression Clinical and Research Program, Massachusetts General Hospital. Dr. Petersen compared 3 types of psychotherapy: · Psychodynamic: cathartic expression of aggression, decrease superego demands · Cognitive: identify distorted automatic negative thoughts · Interpersonal: identify interpersonal problems, correct maladaptive relations, increase social adaptability Empirical support exists for all 3 psychotherapies, though there’s stronger support for cognitive behavior therapy (CBT) and interpersonal therapy (IPT). All 3 require long-term therapy, which may make patients feel less optimistic about results; however, patient involvement is required. Dr. Petersen noted that patients must be careful in choosing a therapist since levels of competency vary. It is also difficult to standardize treatment and measure therapists’ adherence to treatment protocols. And unlike in pharmacotherapy studies, it is difficult to create a placebo control to assess efficacy. Dr. Petersen listed the following as important aspects of CT: · Collaborative therapist-patient alliance · Fostering of ability of patient to use skills independently · Structuring sessions through agenda settings · Consistent measurement of symptoms The most important components of CT are referred to as the 3 Es: · Exploration of patient’s personal beliefs · Examination of evidence supporting/refuting beliefs · Experimentation of test beliefs, data gathering, activity scheduling Even though CT involves homework assignments (journals, activity scheduling form, dysfunctional-thought recording), CT is generally short term. Over 80 trials support CT’s efficacy, with CT equal to SSRI + augmentation in severely depressed outpatients and equal to MAOIs in atypical depression. Interpersonal psychotherapy (IPT) involves connection between life events and psychopathology, with emphasis on defining depression as a medical illness, role playing, and communication/decision analysis. It is less structured than CT. Sessions focus on role transitions, grief, interpersonal conflicts, and interpersonal deficits. IPT is equally effective in mild depression as drug treatments. In severe depression, IPT was equal to imipramine. Continuation of IPT confers long-term improved social functioning. Device-Based Treatment for Depression A. John Rush, MD, Professor, Department of Psychiatry. University of Texas, Southwestern Medical Center Dr. Rush began his presentation by discussing electroconvulsive therapy (ECT). In ECT, seizure initiation in the prefontal cortex is critical to efficacy. ECT is the most effective available treatment for depression, though its use is limited by its cognitive side effects (anterograde amnesia, retrograde amnesia). To improve the side-effect profile of ECT, ultrabrief pulse right unilateral ECT is being explored. This involves a standard pulse with increased wavelength to increase the efficiency of stimulation. Repetitive transcranial magnetic stimulation (rTMS) is a novel brain stimulation approach that uses a pulsed magnetic field to depolarize neurons in a focal area to generate electrical currents in the brain. The rationale for this approach is that depression represents a dysregulation of the prefrontal cortex and limbic regions. rTMS corrects this dysregulation. So far, uncontrolled studies indicate an advantage for rTMS, with a weighted effect size of 1.37 (>1 is a robust-size effect). However, in controlled studies, the results were not as convincing, with a weighted effect size of 0.67. This may have been because of the heterogeneity across studies and dubious controls. The status of rTMS is that it has variable and modest antidepressant effects with long-term effects not well defined. Magnetic seizure therapy (MST) induces more focal seizures in the right frontal area of the brain in order to retain the efficacy of ECT without cognitive side effects. This focused seizure induction may avoid spread to the hippocampus. In studies, MST produced less amnesia than ECT and reduced depression symptoms, using the Beck Depression Inventory and Hamilton Depression scales, as early as 1 week posttreatment. Dr. Rush then devoted considerable discussion
to vagus nerve stimulation (VNS) for depression. Currently, VNS
is approved for epilepsy-seizure reduction; however, it increases
the turnover for the neurotransmitters norepinephrine, dopamine,
and serotonin and has no cognitive side effects. VNS involves the
use of a pacemaker-like pulse generator that provides mild electrical
pulses to the left vagus nerve in the neck for transmission to the
brain. It is on for 30 seconds at 5-minute intervals, 24 hours a
day. Patient adherence is 100%. It has been implanted in over 25,000
patients worldwide. A 2-year clinical study of VNS (D-01) demonstrated
that patients maintained their response and remission rates during
2 years of VNS therapy. In a subsequent study (D-02), long-term
outcome demonstrated increasing response and remission with VNS
over time, with voice alteration as the most common adverse effect.
Currently, VNS is approved for depression in Europe and Dr. Rosenbaum inquired about the possibility of determining which patients would be best suited for the various device-based treatments described above. According to Dr. Rush, “we don’t have the technology to determine which patients are best suited for these techniques. For example, VNS at 3 months shows improvement; longer term outcome may show even better [results].” After Dr. Rush’s presentation, he was queried as to who would be responsible for managing this invasive treatment with altered-voice side effect. He indicated that a psychiatrist, not a PCP, would prescribe its use for treatment-resistant patients. The voice alteration would only occur during the 30-second stimulation period. To his knowledge, no one has discontinued therapy due to altered voice. The Future of Treatment-Matching in Depression Steven P. Roose, MD, Professor of Clinical Psychiatry, College of Physicians & Surgeons, Columbia University. “The fact that it takes a long time to learn
how to treat depression shouldn’t be a surprise. Patients are a
heterogeneous group,” was how Dr. Roose began his discussion on
matching treatments to patients. There are 2 approaches to treating
depression: algorithims and matching. Dr. Roose prefers matching
patients to specific treatments. Treatment response is moderated
by age, gender, biological subtype, early life stress, or phenomenological
subtypes. Studies have indicated that there is little difference
in response and remission in young and old depressed patients. However,
there are sex differences. For example, depression affects more
women, and 90% of suicides in the The discussion then focused on 2 trials by the Danish University Antidepressant Group (DUAG I & II). Both trials compared the efficacy of a TCA to 2 different SSRIs in patients with melancholic features of depression. The study indicated that SSRIs had an advantage over TCAs in cardiovascular effects; however, efficacy was no better than TCAs, or sometimes worse. This superior efficacy on the part of TCAs in depressed patients with melancholic subtype has been confirmed in other studies. According to Dr. Roose, looking at the phenomenology of patient subtypes can be an important predictor of treatment type. At the end of the presentation, Dr Roose stated that “it’s not what treatments we have available, but how effectively we use them.” Beyond Serotonin: New Treatments for Depression Chair: Jack M. Gorman, MD, Esther and Joseph Klingenstein Professor and Chair, Department of Psychiatry, Mount Sinai School of Medicine Although selective serotonin reuptake inhibitors (SSRIs) are usually successful in treating depression, at least 30% of patients do not respond to a first course of treatment. An often-used strategy for handling this problem is prescribing additional medications to enhance or potentiate response. Although this was once criticized as “polypharmacy,” it is now recognized that a judicious combination of medications may improve SSRI response. Combining Treatments to Enhance SSRI Response Jack M. Gorman, MD According to the World Health Organization, depression
is the second most disabling condition in the world. In the After the presentation, Dr. Gorman was approached concerning the use of vagus nerve stimulation in general as a convenient and practical therapy. He felt it is useful for refractory depression and that its use is not as complex as it once sounded, since the implant procedure is minor. What Should We Do With SSRI Nonresponders? Michael E. Thase, MD Professor of Psychiatry, University of Pittsburgh Medical Center Psychiatrists have 2 main choices when an initial antidepressant trial doesn’t lead to sufficient symptom relief: 1) switch medications or 2) add something new to try to augment the ineffective antidepressant. Switching may be similarly dichotomized to either within-class or across-class strategies. Most antidepressant nonresponse can be explained by nonadherence, latent bipolarity, latent psychosis, or occult physical illness. Psychosocial issues, such as marital discord, lack of social support, limited resources, maladaptive interpersonal style, demoralization, or noncompliance, can also play a part in nonresponse. A reasonable strategy for resistant depression is switching within the same class of antidepressant; one SSRI failure should not dictate a class switch for a first treatment failure. Studies indicate a 50% chance of success for a switch within class. Another possibility for treatment failure is to switch to a new drug class. This has advantages over augmentation, a lower risk of drug-drug interactions, and is less expensive; it is also simpler to use one treatment. Augmentation is also a valid option for a first treatment failure since onset can be faster, it avoids a washout period for the first drug, and the drugs may have complementary mechanisms. Pindolol augmentation is good for easy-to-treat patients, but not for nonresponders. Buspirone augmenation is popular and safe, though efficacy is unproven. Atypical antidepressants are now preferred and are increasing in popularity, although long-term efficacy is still unceratin. A study by Shelton RC, et al demonstrated that fluoxetine augmented with olanzapine led to significantly greater response on the MADRS than with either drug alone (Am J Psychiatry. 2001;158:131-134). Combination of the TCA desipramine with fluoxetine led to greater improvement in depression scores and outstanding remission than either drug alone (Nelson JC, et al. Arch Gen Psychiatry. 1991;48:303-307). Mirtazapine augmentation to failed SSRI led to greater response and remission rates than monotherapy without mirtazapine (Carpenter LL, et al. Biol Psychiatry. 2002;51:183-188). Dr. Thase ended his presentation by stating that we should “try not to say that the patient failed treatment, but that the treatment failed the patient.” The Relationship Between Substance P, Serotonin, and Other Neurotransmitter Systems Linda L. Carpenter, MD, Department of Psychiatry and Human Behavior, Brown University Medical School At present, all FDA-approved medications for the treatment of major depression are believed to act principally on the monoaminergic neurotransmitter systems. However, recent evidence regarding the antidepressant potential of compounds that selectively block a neurokinin (NK1) receptor has inspired research into understanding the relationship between neuropeptide substance P and monoamines. There is much evidence on the role of monoamine neurotransmitters (serotonin, norepinephrine, dopamine) in depression. Substance P (SP) was discovered in 1931, and its potential for depression was demonstrated in 1988. It is found in the brain locations responsible for emotional regulation (the hippocampus, amydgala). SP binds to the NK1 receptor on postsynaptic neurons. Antagonism of the SP binding to NK1 lead to increased serotonin firing. In a study by van der Hart, et al. (Mol Psychiatry. 2002;7:933). SP antagonists reversed stress-induced weight loss in a small animal. In another animal study, SP antagonist treatment significantly reduced anxiety-like symptoms (Santarelli, et al. PNAS. 2001;98:1912). In patients with PTSD, SP was elevated. Dr. Carpenter described the rationale for the clinical development of SP antagonists: · SP and SP antagonists have multiple sites of action in the brain regions relevant to mood and anxiety · SP antagonism or inactivation of the NK1 receptor decreased stress and anxiety-like behavior · Decrease in stress/anxiety-like behavior correlates with increased activity of serotonin neurons and antidepressant drug efficacy Clinical Experience With Substance P Antagonists in Depression and Associated Anxiety. K. Ranga Rama Krishnan, MD, Professor and Chair, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center Several clinical trials have examined the potential of SP antagonists (SPAs) in the treatment of depression. In phase 2 trials, therapy with the SPAs aprepitant and another compound resulted in improvements in depression and anxiety symptoms comparable to SSRIs, establishing a proof of the concept that the inhibition of the SP-NK1 receptor pathway may be a potentially useful novel treatment option for managing patients with depression. Dr. Krishnan presented the failed trials of aprepitant as a way of highlighting the complexities in bringing a compound through the drug development process. The SPA aprepitant worked in animal models, but not in humans. Currently, aprepitant is indicated for chemotherapy-induced nausea, at lower doses. As Dr. Krishnan mentioned, “for every drug approved, thousands are discarded.” This rare look at the failure of a potential drug compound for depression will allow future trials to focus on the identification of appropriate patients and drug regimens.
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