The following is a transcript from a web-based CME-certified multimedia activity. Interactivity applies only when viewing the activity online.

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1 Presentation 1 The following is a transcript from a web-based CME-certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by an educational grant from Otsuka America Pharmaceutical, Inc. Dr. Thase: Hello, this is Dr. Michael Thase from the Perelman School of Medicine and the Departments of Psychiatry at the University of Pennsylvania in Philadelphia, as well as the Philadelphia Veterans Affair Medical Center. Welcome to this educational activity on major depressive disorder management. After completing the activity, access the post-test and evaluation form by clicking the red Credit button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you and to participate in the Ask the Faculty. and evaluation for CME credit: 1

2 Presentation 1 Disclosures Course Director and Interviewee Michael E. Thase, MD, has a financial interest/relationship or affiliation in the form of: Consultant for Alkermes; AstraZeneca; Bristol-Myers Squibb; Cerecor Inc.; Eli Lilly and Company; Dey Pharma, L.P. (Mylan Specialty L.P); Forest Laboratories, Inc.; Gerson Lehrman Group, Inc.; Guidepoint Global, LLC; Lundbeck; MedAvante, Inc.; Merck & Co., Inc. (formerly Schering Plough and Organon); Neuronetics; Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen); Otsuka Pharmaceutical Co., Ltd.; Pamlab; Pfizer Inc. (formerly Wyeth Ayerst Pharmaceuticals); PGx, Inc.; Shire; Sunovion Pharmaceuticals Inc.; Supernus Pharmaceuticals; Takeda Pharmaceuticals U.S.A., Inc.; and Transcept Pharmaceuticals. Grant/Research Support from Agency for Healthcare Research and Quality; Alkermes; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; Forest Laboratories, Inc.; Otsuka Pharmaceutical Co., Ltd.; PharmaNeuroBoost; and The National Institute of Mental Health. Shareholder in Equity Holdings: MedAvante, Inc. Other Financial or Material Support from Royalties: American Psychiatric Foundation; Guilford Publications; Herald House; and W. W. Norton & Company, Inc. CME Reviewer Eric I. Rosenberg, MD, MSPH, FACP Associate Professor and Chief Division of General Internal Medicine University of Florida College of Medicine Gainesville, Florida Eric I. Rosenberg, MD, MSPH, FACP, has no financial interests/relationships or affiliations in relation to this activity. Medical Directors Kirk A. Tacka, PhD PVI, PeerView Institute for Medical Education Kirk A. Tacka, PhD, has no financial interests/relationships or affiliations in relation to this activity. Monique Johnson, MD PVI, PeerView Institute for Medical Education Monique Johnson, MD, has no financial interests/relationships or affiliations in relation to this activity. and evaluation for CME credit: 2

3 Presentation 1 Initial Management Strategies and Assessing Treatment Response in MDD DSM: Diagnostic and Statistical Manual of Mental Disorders; MDD: major depressive disorder; MDE: major depressive episode. 1. American Psychiatric Association. Highlights of Changes from DSM-IV-TR to DSM-5. to-dsm-5.pdf. Accessed August 19, Dr. Thase: So let s talk first about major depressive disorder and our goal to treat to remission and to help patients gain functional recovery. I think it s noteworthy that 2013 marked the introduction of the newest edition of the DSM, and that s the DSM-5. Importantly, the basic definition of a major depressive episode and major depressive disorder did not change; the core criteria and the requisite duration of symptoms remain the same. There have been some noteworthy revisions, however, and I think most controversially has been the addition of a term with mixed features as a specifier, which means that the bipolar spectrum has now moved into the major depressive disorder domain because you can diagnose patients with one or two or three mixed features as having this unique specifier and perhaps then tag that patient for potentially being at greater risk for developing bipolar disorder or developing mood excursions on antidepressants. and evaluation for CME credit: 3

4 Presentation 1 I think the other controversial change has been the exclusion of the bereavement disorder exclusion criterion. And namely, that there has been a whole generation of research now that has demonstrated that major depressive episodes that develop within the context of bereavement do not differ qualitatively or quantitatively from major depressive episodes that develop at times of other kinds of serious adverse life events. and evaluation for CME credit: 4

5 Presentation 1 SNRIs: selective norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors. 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: Now, the past few years have been a time of introduction of several new antidepressants, and if we look at the next slide, we re looking at our generally considered first-line antidepressants, the SSRIs and the SNRIs. and evaluation for CME credit: 5

6 Presentation 1 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: I think some people would go ahead and add bupropion and then mirtazapine to the list. And then this leaves us with serotonin-modulating medications, such as nefazodone and trazodone, that are seldom used today but still available in the United States. and evaluation for CME credit: 6

7 Presentation 1 TCA: tricyclic antidepressant. 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: Most would agree that the tricyclic antidepressants and the monoamine oxidase inhibitors are clearly second- or third-line medications. The slide summarizes the list of the tricyclics, as well as the MAOIs and the kind of novel MAOIs, including the transdermally delivered form of selegiline, as well as the [reversible] selective monoamine oxidase A inhibitor, or REMA, moclobemide, which is only available in Canada, Mexico, and other places outside of the US. and evaluation for CME credit: 7

8 Presentation 1 5-HT: 5-hydroxytryptophan; HAM-D: Hamilton Depression Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale. 1. Khan A et al. J Clin Psychiatry. 2011;72: Rickels K et al. J Clin Psychiatry. 2009;70: Dr. Thase: Now into this kind of mixture of first- and second-line, [as well as] third-line medications, we have three new medicines, the first being vilazodone, which was introduced in Vilazodone is distinguished by being a serotonin reuptake inhibitor that is also a potent partial agonist at the serotonin [5-HT] 1A receptor. There s no doubt that this is an effective antidepressant. And typically in order to get to the 40-mg/day therapeutic dose, you need to start at 10 mg for at least a week and then another week or two at 20 mg before you can get up to 40 mg/day in order to help reduce the otherwise unacceptably high rate of GI side effects. and evaluation for CME credit: 8

9 Presentation 1 SDS: Sheehan Disability Scale. 1. Asnis GM et al. J Clin Psychiatry. 2013;74: Auclair AL et al. Neuropharmacology. 2013;70: Dr. Thase: I think another novel medication finally got to the US market in December of 2013 and that is levomilnacipran in a sustained-release formulation. Now this medicine is a serotonin-norepinephrine reuptake inhibitor and it is the first member of the SNRI family that is more noradrenergic than it is serotonergic, or at least disproportionately so. And so here we have a medicine that has established efficacy in a dose range of 40 to 120 mg/day. I think that in my practice I rarely see the 40-mg dose work; I typically need to use higher doses, but if you're using it earlier in a treatment sequence, I think you will see some easier-to-treat patients who are responsive to the 40-mg dose. and evaluation for CME credit: 9

10 Presentation 1 1. Alvarez E et al. Int J Neuropsychopharmacol. 2012;15: Henigsberg N et al. J Clin Psychiatry. 2012;73: Katona C et al. Int Clin Psychopharmacol. 2012;27: Boulenger JP et al. Int Clin Psychopharmacol. 2014;29: McIntyre RS et al. Int J Neuropsychopharmacol. 2014;17: Katona C et al. Int Clin Psychopharmacol. 2012;27: Dr. Thase: The other 2013 antidepressant [that] came to us is vortioxetine. Vortioxetine is a serotonin reuptake inhibitor that has a suite of other effects, including agonism and partial agonism at serotonin [5-HT] 1A and 1B and antagonism at serotonin 3 and serotonin 7 receptors. It has a therapeutic range between 5 and 20 mg worldwide. In the United States, the 5-mg dose was not established as effective, so the FDA approved the 10- and 20-mg doses. And of course, the suite of actions of this drug is such that it conveys the same general therapeutic properties of other serotonin reuptake inhibitors. But some of the potential clinical consequences that come from this group of secondary actions might include, at lower doses, a lower incidence of sexual side effects; or, for patients who have significant cognitive impairment, this may have more of a cognitive enhancing effect than some other antidepressants. And so these are not part of the official indication for this medication. These are still topics that are under intense investigation. and evaluation for CME credit: 10

11 Presentation 1 1. Deardorff WJ et al. Expert Opin Pharmacother. 2014;16:1-18. Narrator: The newer antidepressant agents promise to offer benefits not fully realized with many current antidepressants. These benefits include having mechanistic activity that is novel or that targets neurotransmitter systems in multiple ways; possessing enhanced selectivity or potentially higher potency; and having better tolerability afforded by fewer side effects commonly associated with antidepressant agents. Currently, for the three newer antidepressants reviewed in this CME activity vilazodone, levomilnacipran, and vortioxetine data support efficacy in the treatment of major depressive disorder, but data comparing them with other antidepressants are currently lacking. and evaluation for CME credit: 11

12 Presentation 1 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: The next slide simply summarizes how we ascertain an adequate treatment trial. If the patient is not obtaining an adequate response despite good tolerability after 4 weeks, consider increasing the dose to the maximum end of the therapeutic range, knowing that for many of our medications, we do not have clearly established doseresponse relationships. Of course when patients respond during those first 4 to 8 weeks, you move into the continuation phase of treatment. When patients do not respond, always make sure that you have a good handle on tolerability and side effects and whether the patient is adhering to treatment. Patients tell us we do not ask often enough about medication side effects or deal with those side effects, and that these in turn are one of the major reasons why patients drop out of treatment. and evaluation for CME credit: 12

13 Presentation 1 1. Beck AT et al. Arch Gen Psychiatry. 1961;4: Kroenke K et al. J Gen Intern Med. 2001;16: Hamilton M. J Neurol Neurosurg Psychiatry. 1960;23: Montgomery SA, Åsberg M. Br J Psychiatry.1979;134: Rush AJ et al. Biol Psychiatry. 2003;54: Dr. Thase: Now there s some evidence to suggest that it s hard to tell the difference between a good enough, but not complete, response and a full remission based on simple general clinical inquiry within a short medication monitoring visit. And for this reason, one of the aspects of management these days has been to include certain assessment tools as standard parts of the clinical evaluation. All of these scales really do a good enough job calibrating whether the patient has had a significant relief of symptoms. So it doesn t matter which of these scales that you use; it matters more that you use one and that you stick with it. And I think you will find that if you start to consistently inquire about side effects, consistently inquire about adherence, and document the level of ongoing symptoms, that indeed you will find that your patients have the best chance of getting to the goal of a symptomatic remission and a functional recovery. and evaluation for CME credit: 13

14 New and Emerging Strategies in MDD to Optimize Treatment Response MDD: major depressive disorder. 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: Why don't we move on now and talk about new and emerging strategies to optimize treatment response. So here we re talking about patients that have gone through the process. We have made sure that they ve had an adequate and full trial of treatment, that they're adherent to that medication, and they are not responding to it. and evaluation for CME credit: 14

15 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: And so one of the initial considerations is adding psychotherapy to the treatment regimen. Other possibilities might be to increase the dose [so that it is optimal]. And so the remaining three strategies I think of [having] greatest utility in my practice would be switching to a completely different antidepressant. And this is something I do more when the patient has run into significant tolerability problems or has flatly had no benefit whatsoever despite a full and maximum trial. Another possibility would be to use a pharmacologic adjunct to add to the antidepressant medication. This is a preferred strategy when the first medicine is well tolerated, when there s been some hint of improvement but you just haven't gotten there, and when there s urgency for the patient to get better as quickly as possible. The final strategy to talk about here is combining antidepressants. And generally this is done with two dissimilar antidepressants so that you can capitalize on the possibility of unique pathways to benefit. and evaluation for CME credit: 15

16 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; Dr. Thase: Why don't we spend a little time looking at each of these possible strategies, starting with the APA practice guidelines assessment of the utility of these? Psychotherapy: There are positive studies of the adjunctive use of psychotherapy in the context of antidepressant nonresponse. The three most commonly considered medication strategies are adding a second-generation or atypical antipsychotic, adding a mood stabilizer (and in this case, it would be lithium salts), and three, adding a form of thyroid hormone. Although questions pertaining to how long those medicines should be continued when they work continue to be vexing. and evaluation for CME credit: 16

17 HAM-D: Hamilton Depression Rating Scale; QIDS-SR16: 16-Item Quick Inventory of Depressive Symptoms Self-Rated. 1. Nierenberg AA et al. Am J Psychiatry. 2006;163: Dr. Thase: The next slide comes from the STAR*D study, and this is a summary of the STAR*D substudy that compared adjunctive treatment with either lithium or thyroid hormone in patients who had not obtained adequate benefit from sequential trials of firstand second-line antidepressants. And you can see that neither treatment was great in terms of getting patients to remission. Lithium and thyroid were comparable in this regard. But in terms of tolerability, there was a real advantage for thyroid hormone over lithium salt, so more patients got a recommended length of treatment at a recommended dose in the thyroidhormone arm. Since lithium s utility is based in part on how well the treatment is implemented, it was the loser in this study in terms of measures of treatment adherence or treatment implementation compared to thyroid hormone. and evaluation for CME credit: 17

18 1. Rosenthal LJ et al. Am J Psychiatry. 2011;168: Uzzan B et al. Clin Endocrinol Metab. 1996;81: Cappola AR et al. JAMA. 2006;295: Narrator: In euthyroid patients, T3 can induce hyperthyroidism, which may worsen preexisting hypertension, tachycardia, and hyperglycemia. Additionally, hyperthyroidism is associated with reduced bone mineral density and increased risk of osteoporosis, especially in postmenopausal women, and an increased risk of atrial arrhythmias. In general, patients started on T3 augmentation for a psychiatric disorder should be monitored in the same manner as patients treated with T3 for hypothyroidism, including consultation with an endocrinologist. It is unclear how these patients would be monitored from a biochemical standpoint. and evaluation for CME credit: 18

19 1. Nelson JC, Papakostas GI. Am J Psychiatry. 2009;166: Dr. Thase: In the modern era, there is the most evidence for adjunctive treatment with second-generation antipsychotics. And the next two slides summarize the state of the evidence as of a few years ago. In the first panels you're going to see the results for olanzapine in combination with fluoxetine. And you can see this was a proven treatment strategy. And then in the second plot, you can see the evidence from the three studies that were done with risperidone. Again, there is a confirmed benefit for risperidone of about the same magnitude of that of olanzapine. and evaluation for CME credit: 19

20 1. Nelson JC, Papakostas GI. Am J Psychiatry. 2009;166: Dr. Thase: And then if we go on to the next slide, you will see the studies of quetiapine, similarly documenting confirmed benefit. And then [you also see] the studies documenting aripiprazole. Now of these treatment strategies olanzapine added to fluoxetine [in combination], [extended-release] quetiapine added to ongoing antidepressants, and aripiprazole added to ongoing antidepressants all have received FDA approval for this indication. and evaluation for CME credit: 20

21 1. Nelson JC, Papakostas GI. Am J Psychiatry. 2009;166: Narrator: Side effects commonly associated with atypical antipsychotics include sedation, extrapyramidal symptoms, weight gain, increased diabetes risk, and dyslipidemia. Serious adverse events include neuroleptic malignant syndrome, seizures, and tardive dyskinesia. In the previously mentioned meta-analysis of trials using augmentation with atypical antipsychotics for the treatment of acute depression, discontinuation rates of adverse events were higher for atypical agents than for placebo (odds ratio = 3.91, 95% CI = , P <.00001), and the number needed of harm for adverse events serious enough to warrant discontinuation was 17. We have few data to inform on the efficacy and safety of the atypicals during continuation and maintenance treatment in major depression. We also have only limited data on the effective dosage range for atypical antipsychotics used as augmentation in depression. It is important to compare the efficacy and safety of using atypical antipsychotics augmentation with other less expensive strategies, given the safety and cost issues. and evaluation for CME credit: 21

22 ADT: antidepressant therapy; BREX: brexpiprazole; MADRS: Montgomery Åsberg Depression Rating Scale. 1. Thase ME et al. 22nd European Congress of Psychiatry (EPA 2014). Abstract EPA Thase ME et al. APA Abstract 128. Dr. Thase: Now there is one other compound that is being investigated for this particular indication, adjunctive therapy, and this is a drug known as brexpiprazole. I can speak of this with some familiarity because I ve been one of the lead investigators since the beginning of the series of trials that are now under review or that soon will be under review by the FDA. and evaluation for CME credit: 22

23 AE: adverse event; SDS: Sheehan Disability Scale. 1. Thase ME et al. EPA Abstract EPA Thase ME et al. APA Abstract 128. Dr. Thase: The next slide really summarizes the results of one of the positive trials. This is a study using the 2-mg dose of brexpiprazole. And as you can see, at the end of 6 weeks of adjunctive treatment there was an advantage for the active drug over the adjunctive placebo. And this is really comparable to that of aripiprazole with, in this study, a relatively low incidence of akathisia and a good overall tolerability profile. and evaluation for CME credit: 23

24 NMDA: N-methyl-D-aspartate. 1. Murrough JW et al. Am J Psychiatry. 2013;170: Dr. Thase: There is a great unmet need for alternative treatments for patients who have not responded to our known, established, first-, second-, and third-line treatments. And one of the most exciting stories in this area represents work that is done with ketamine and drugs like ketamine. These drugs are NMDA receptor antagonists, and it is remarkable that these medications typically all show therapeutic effects within 24 hours of exposure. Now ketamine has been administered as an intravenous treatment. A single dose results in about a 50[%] to 60% response rate in people who have been refractory often to multiple other interventions. And when people respond to this medication, they typically benefit for 4, 5, 6, 7 days sometimes even longer. So I think there is reason to be hopefully optimistic that there could be interesting new developments in terms of ketamine and ketamine-like drugs, glutamatergic antidepressants, as novel strategies for our most difficult-to-treat patients. and evaluation for CME credit: 24

25 1. Murrough JW et al. Am J Psychiatry. 2013;170: Narrator: Ketamine is associated with sympathomimetic effects, such as a mild to moderate increase in heart rate, blood pressure, and cardiac output. Perceptual disturbances, such as floating-in-space sensations and/or out-of-body experiences, can occur, but these are usually mild and do not last long beyond the infusion. Use is contraindicated in those with hypertension and glaucoma. Caution should be exercised when using in patients with coronary artery disease. Drug drug interactions that are severe can occur with MAOIs, and moderate interactions can occur with antihypertensive agents, thyroid hormone, and anxiolytic agents. Ketamine should be administered in a highly monitored inpatient setting with appropriate airway equipment in place in case of over-sedation. and evaluation for CME credit: 25

26 1. Popp D et al. New Clinical Drug Evaluation Unit 53rd Annual Meeting (NCDEU 2013). Poster Finzi E et al. NCDEU Poster Liebowitz M et al. NCDEU Poster 55. Dr. Thase: With that in mind, the next slide summarizes some other novel treatments. So one [is] an alternate approach interfacing with the NMDA receptor, namely through the glycine site, a drug called GLYX-13, for which there has been positive evidence. I think another interesting possibility relates to the use of botulinum toxin as an injectable treatment. Here, however, the idea is if you paralyze the glabellar muscles, you affect the ability to feel negatively to frown and so forth and there is evidence from several studies suggesting positive therapeutic effects on mood and even relief of depression. And then lastly, a drug known as PH10 [was] first presented last year at the NCDEU meeting. And this drug, interestingly, engages chemoreceptors through nasal inhalation and may stimulate the process that leads to antidepressant response actually through olfactory cortical mechanisms. and evaluation for CME credit: 26

27 Dr. Thase: I think to summarize today s presentation, the first order of business is that we ve got to get treatment going and implement it fully with the goal of full symptomatic remission and functional recovery. The best way to do this is to see patients frequently, address their side effects, ask about their adherence, and follow their symptomatic status with validated, easy-to-use scales. When patients respond to treatment, move them on to continuation therapy. For patients who do not obtain this level of response, there are a variety of strategies available, including psychotherapy and alternate pharmacotherapies. But generally we re talking about either adding or switching. And I think lastly that there is recognition that once we exhaust the therapeutic potential of strategies that target monoamines that we do need to consider other possible targets. And with this in mind, there are quite exciting novel research mechanisms being investigated. and evaluation for CME credit: 27

28 Narrator: This activity has been jointly provided by the University of Florida College of Medicine and PVI, PeerView Institute for Medical Education. and evaluation for CME credit: 28