- Email: [email protected]
C.14.01 DEBATE: Managing inadequate response to initial antidepressant therapy: to switch or not to switch?
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C.14. Opportunities and challenges in the management of patients with major depressive disorder
the NMDA glycine modulatory site. The results have been variable, possibly due to heterogeneity in the trials with respect to whether patients were administered concomitant typical or atypical antipsychotics, but a recent meta-analysis of 26 placebocontrolled trials with glycine, D-cycloserine, D-serine, sarcosine, and D-alanine identified significant but modest improvements in total psychopathology, depressive symptoms, negative symptoms, cognitive symptoms, positive symptoms, and general psychopathology (in order of effect size) [1]. Another approach to targeting the glycine modulatory site relies on the use of glycine reuptake inhibitors (GRIs). Sarcosine-derived GRIs have been shown to have undesirable side-effects, including ataxia, hypoactivity and decreased respiration, and this has prompted the development of novel classes of non-sarcosine-based GRIs. Several such compounds are at various stages of clinical development. Another potential therapeutic strategy is based on agents that are intended to ameliorate the downstream effects of the putative NMDA receptor dysfunction, such as mGluR2/3 agonists, which appear to act presynaptically in reducing glutamate release in prefrontal cortex. A phase II study with the mGluR2/3 agonist prodrug LY2140023, used as monotherapy in acutely relapsing subjects, showed clinical efficacy similar to that of olanzapine, with reduced incidence of metabolic side effects [2], although a larger second study failed to replicate the finding [3].
Two broad switching strategies are available: switching to another antidepressant of the same class known as ‘within-class’; and switching to a different class of antidepressant or ‘across-class’. A meta-analysis of data from four clinical trials compared these two strategies in patients with non-response to a selective serotonin reuptake inhibitor (SSRI), and showed that those switched acrossclass were more likely to experience remission than those switched within-class (numerically small, but statistically significant difference) [1]. Conversely, the merit of within-class switching has been suggested by the results of several open-label studies, which found that despite non-response to one SSRI, the chance of responding to a second SSRI was between 40% and 70% [2]. The current debate concerns whether TRD should be treated with an across-class or a within-class switching strategy. Guidelines almost uniformly support the across-class switch, and Dr Thase will argue that this recommendation is correct. Dr Montgomery will argue that across-class switching gives no advantage, as demonstrated in a retrospective meta-analysis [3], and that it may even result in a significantly worse outcome than persisting with the same class. At present, neither a switch within-class nor across-class is clearly supported by the data as the best strategy when inadequate response to initial antidepressant therapy occurs, and debate continues about this important topic.
References
References
[1] Tsai, G.E., Lin, P.Y., 2010 Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16, 522–537. [2] Patil S.T., Zhang L., Martenyi F., Lowe S.L., Jackson K.A., Andreev B.V., Avedisova A.S., Bardenstein L.M., Gurovich I.Y., Morozova M.A., Mosolov S.N., Neznanov N.G., Reznik A.M., Smulevich A.B., Tochilov V.A., Johnson B.G., Monn J.A., Schoepp D.D., 2007 Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized phase 2 clinical trial. Nat Med 13, 1102– 1107. [3] Eli Lilly and Company, 2009 Lilly announces inconclusive phase II study results for mGlu2/3 at the International Congress on Schizophrenia Research. http://newsroom.lilly.com/releasedetail.cfm ?releaseid=373650.
[1] Papakostas, G.I., Fava, M., Thase, M.E., 2008 Treatment of SSRIresistant depression: a meta-analysis comparing within- versus acrossclass switches. Biol Psychiatry 63, 699–704. [2] Thase, M.E., Rush, A.J., 1997 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 58 Suppl 13, 23−29. [3] Souery, D., Serretti, A., Calati, R., Oswald, P., Massat, I., Konstandinidis, A., Linotte, S., Bollen, J., Demyttenaere, K., Kasper, S., Lecrubier, Y., Montgomery, S., Zohar, J., Mendlewicz, J., 2011 Switching antidepressant class does not improve response or remission. J Clin Psychopharmacol in press.
Disclosure statement: Dr. Lieberman serves on the Scientific Advisory Boards for Bioline, Pierre Fabre and PsychoGenics and he receives grant support from Allon, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, F. Hoffman-La Roche LTD, Sepracor (Sunovion) and Targacept. He does not receive direct financial compensation or salary support for participation in any of these research or advisory board activities. He also serves on the Scientific Advisory Board for Intracelllular Therapies and holds a patent from Repligen.
C.14. Opportunities and challenges in the management of patients with major depressive disorder C.14.01 DEBATE: Managing inadequate response to initial antidepressant therapy: to switch or not to switch? S. Montgomery1 ° , M.E. Thase2 . 1 Imperial College, University of London, London, United Kingdom; 2 Department of Psychiatry, University of Pennsylvania, Philadelphia, USA Treatment-resistant depression (TRD) is a more serious condition than major depressive disorder (MDD) itself, and is commonly encountered in patients with MDD. There are few studies investigating treatment of resistant depression.
Disclosure statement: Stuart Montgomery has received honoraria from, or participated in advisory boards for: AstraZeneca, Bionevia, BristolMyers Squibb, GlaxoSmithKline, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis and Wyeth. Michael E. Thase is or has been an advisor/consultant to, on the speaker bureaus of, received research support, or received royalties/patent or other income from: American Psychiatric Publishing Inc., AstraZeneca, Bristol-Myers Squibb, Cephalon Inc., Cyberonics Inc., Eli Lilly, Forest, GlaxoSmithKline, Guildford Publications, Herald House, Janssen Pharmaceutica, MedAvante Inc., Neuronetics Inc., Novartis, Organon International, Sanofi-Aventis, Schering Plough, Sepracor Inc., Shire US Inc., Supernus Pharmaceuticals, WW Norton and Co. Inc. and Wyeth.
C.14.03 A review of recent advances in evidencebased medicine in MDD: strategies for the unresponsive patient M. Bauer1 ° . 1 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Dresden, Germany Major depressive disorder (MDD) is a severe, chronic and disabling disease associated with considerable morbidity and mortality. The efficacy of currently available antidepressants is similar across the classes, with response rates ranging from 50 to 75%. Hence, despite the availability of many pharmacological treatments, non- or partial-response to treatment is common. Pharmacological treatment options available for unresponsive patients
C.14. Opportunities and challenges in the management of patients with major depressive disorder
the NMDA glycine modulatory site. The results have been variable, possibly due to heterogeneity in the trials with respect to whether patients were administered concomitant typical or atypical antipsychotics, but a recent meta-analysis of 26 placebocontrolled trials with glycine, D-cycloserine, D-serine, sarcosine, and D-alanine identified significant but modest improvements in total psychopathology, depressive symptoms, negative symptoms, cognitive symptoms, positive symptoms, and general psychopathology (in order of effect size) [1]. Another approach to targeting the glycine modulatory site relies on the use of glycine reuptake inhibitors (GRIs). Sarcosine-derived GRIs have been shown to have undesirable side-effects, including ataxia, hypoactivity and decreased respiration, and this has prompted the development of novel classes of non-sarcosine-based GRIs. Several such compounds are at various stages of clinical development. Another potential therapeutic strategy is based on agents that are intended to ameliorate the downstream effects of the putative NMDA receptor dysfunction, such as mGluR2/3 agonists, which appear to act presynaptically in reducing glutamate release in prefrontal cortex. A phase II study with the mGluR2/3 agonist prodrug LY2140023, used as monotherapy in acutely relapsing subjects, showed clinical efficacy similar to that of olanzapine, with reduced incidence of metabolic side effects [2], although a larger second study failed to replicate the finding [3].
Two broad switching strategies are available: switching to another antidepressant of the same class known as ‘within-class’; and switching to a different class of antidepressant or ‘across-class’. A meta-analysis of data from four clinical trials compared these two strategies in patients with non-response to a selective serotonin reuptake inhibitor (SSRI), and showed that those switched acrossclass were more likely to experience remission than those switched within-class (numerically small, but statistically significant difference) [1]. Conversely, the merit of within-class switching has been suggested by the results of several open-label studies, which found that despite non-response to one SSRI, the chance of responding to a second SSRI was between 40% and 70% [2]. The current debate concerns whether TRD should be treated with an across-class or a within-class switching strategy. Guidelines almost uniformly support the across-class switch, and Dr Thase will argue that this recommendation is correct. Dr Montgomery will argue that across-class switching gives no advantage, as demonstrated in a retrospective meta-analysis [3], and that it may even result in a significantly worse outcome than persisting with the same class. At present, neither a switch within-class nor across-class is clearly supported by the data as the best strategy when inadequate response to initial antidepressant therapy occurs, and debate continues about this important topic.
References
References
[1] Tsai, G.E., Lin, P.Y., 2010 Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16, 522–537. [2] Patil S.T., Zhang L., Martenyi F., Lowe S.L., Jackson K.A., Andreev B.V., Avedisova A.S., Bardenstein L.M., Gurovich I.Y., Morozova M.A., Mosolov S.N., Neznanov N.G., Reznik A.M., Smulevich A.B., Tochilov V.A., Johnson B.G., Monn J.A., Schoepp D.D., 2007 Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized phase 2 clinical trial. Nat Med 13, 1102– 1107. [3] Eli Lilly and Company, 2009 Lilly announces inconclusive phase II study results for mGlu2/3 at the International Congress on Schizophrenia Research. http://newsroom.lilly.com/releasedetail.cfm ?releaseid=373650.
[1] Papakostas, G.I., Fava, M., Thase, M.E., 2008 Treatment of SSRIresistant depression: a meta-analysis comparing within- versus acrossclass switches. Biol Psychiatry 63, 699–704. [2] Thase, M.E., Rush, A.J., 1997 When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 58 Suppl 13, 23−29. [3] Souery, D., Serretti, A., Calati, R., Oswald, P., Massat, I., Konstandinidis, A., Linotte, S., Bollen, J., Demyttenaere, K., Kasper, S., Lecrubier, Y., Montgomery, S., Zohar, J., Mendlewicz, J., 2011 Switching antidepressant class does not improve response or remission. J Clin Psychopharmacol in press.
Disclosure statement: Dr. Lieberman serves on the Scientific Advisory Boards for Bioline, Pierre Fabre and PsychoGenics and he receives grant support from Allon, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, F. Hoffman-La Roche LTD, Sepracor (Sunovion) and Targacept. He does not receive direct financial compensation or salary support for participation in any of these research or advisory board activities. He also serves on the Scientific Advisory Board for Intracelllular Therapies and holds a patent from Repligen.
C.14. Opportunities and challenges in the management of patients with major depressive disorder C.14.01 DEBATE: Managing inadequate response to initial antidepressant therapy: to switch or not to switch? S. Montgomery1 ° , M.E. Thase2 . 1 Imperial College, University of London, London, United Kingdom; 2 Department of Psychiatry, University of Pennsylvania, Philadelphia, USA Treatment-resistant depression (TRD) is a more serious condition than major depressive disorder (MDD) itself, and is commonly encountered in patients with MDD. There are few studies investigating treatment of resistant depression.
Disclosure statement: Stuart Montgomery has received honoraria from, or participated in advisory boards for: AstraZeneca, Bionevia, BristolMyers Squibb, GlaxoSmithKline, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis and Wyeth. Michael E. Thase is or has been an advisor/consultant to, on the speaker bureaus of, received research support, or received royalties/patent or other income from: American Psychiatric Publishing Inc., AstraZeneca, Bristol-Myers Squibb, Cephalon Inc., Cyberonics Inc., Eli Lilly, Forest, GlaxoSmithKline, Guildford Publications, Herald House, Janssen Pharmaceutica, MedAvante Inc., Neuronetics Inc., Novartis, Organon International, Sanofi-Aventis, Schering Plough, Sepracor Inc., Shire US Inc., Supernus Pharmaceuticals, WW Norton and Co. Inc. and Wyeth.
C.14.03 A review of recent advances in evidencebased medicine in MDD: strategies for the unresponsive patient M. Bauer1 ° . 1 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Dresden, Germany Major depressive disorder (MDD) is a severe, chronic and disabling disease associated with considerable morbidity and mortality. The efficacy of currently available antidepressants is similar across the classes, with response rates ranging from 50 to 75%. Hence, despite the availability of many pharmacological treatments, non- or partial-response to treatment is common. Pharmacological treatment options available for unresponsive patients