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Management of Major Depressive Disorder: The Role of Atypical Antipsychotics

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 23rd Congress of the European College of Neuropsychopharmacology

Amsterdam, The Netherlands / August 28-September 1, 2010

“Severe depression is the most important dimension of a complex and heterogeneous condition that includes anxiety, suicidality and multiple medical comorbidities that are urgent to treat,” according to Dr. Michael E. Thase, Director, Mood and Anxiety Program, and Professor of Psychiatry, University of Pennsylvania, Philadelphia. “You get your best results in the first and second courses of treatment because not only do the chances for remission get worse with each successive course, the opportunity to even help patients get to remission evaporates in a significant 10% to 20% minority of patients who drop out between ineffectively early courses of treatment.”

He noted that it is not that antidepressants are not effective, but that they have significant effects for only a relatively small proportion of patients who have the most severe depressive symptoms. At a very low level of depressive severity, there is little or no evidence that antidepressants contribute anything over and above the placebo effect. They clearly have a large and meaningful effect for patients with more severe symptoms and a smaller effect for patients with less severe depression.

“In the US, second-generation antipsychotics are increasingly used as adjunctive therapy because they work and work quickly,” he confirmed, “and you cannot say that as definitively about any other pharmacologic strategy for patients with difficult-to-treat depression. To date, several atypical antipsychotics have demonstrated efficacy as combination therapy with, or adjunctive to, antidepressants in clinical studies of antidepressant non-responders. They are aripiprazole, olanzapine-fluoxetine combination, extended-release (XR) quetiapine and risperidone.”

He reported that in those studies, the mean difference favoured the adjunctive antipsychotic and in more than half the studies, the findings were statistically significant. The summary conclusion for each of the 4 atypical antipsychotics is one of efficacy and there was probably not a significant difference between the most effective and least effective agents, although they have not yet been tested in direct comparison studies.

Major Depressive Disorder

So far, only quetiapine has demonstrated efficacy as monotherapy for major depressive disorder (MDD). Studies of the XR formulation in treatment-resistant MDD patients have assessed 150 mg/day and 300 mg/day in 4 critical comparisons, Dr. Thase told delegates. The drug-placebo differences at week 6 were statistically significant with both the 150-mg and 300-mg doses more effective than placebo. He added that these trials include the only randomized trial of an atypical antipsychotic vs. an alternate monotherapy and vs. an alternate adjunctive treatment strategy with lithium augmentation.

In that study, 688 patients with a Montgomery-Åsberg Depression Rating Scale (MADRS) score of =25 who failed on =2 antidepressants were given either 300 mg/day adjunct quetiapine XR plus venlafaxine or a selective serotonin reuptake inhibitor (SSRI), quetiapine XR monotherapy, or up to 1.0 mmol/L adjunct lithium. The XR formulation plus venlafaxine and the monotherapy arms were both non-inferior to lithium plus antidepressant, taking multiplicity into account. The changes in MADRS scores from baseline at week 6 was -13.9, -14.7 and -13.0 for quetiapine XR plus antidepressant, XR monotherapy and lithium plus antidepressant groups, respectively. The superiority analysis found no statistical difference, but supported the non-inferior results.

Improvement from baseline in MADRS total score was numerically greater in both XR groups than with lithium plus antidepressant at all time points. Remission rates at week 6 were 21.9%, 18.4% and 22.65% for quetiapine XR plus antidepressant, quetiapine XR monotherapy and lithium plus antidepressant, respectively; response rates at week 6 were 48.2%, 52.6% and 42.6%. The investigators reported that analysis of secondary variables confirmed non-inferiority between the treatment groups.

Dr. Thase added, “Whether quetiapine XR was added to ongoing antidepressant therapy or used as monotherapy, there were significant advantages at days 4 and 8 for the 2 groups that were given that agent. By day 22, the adjunctive therapy continued to show a significant benefit compared to lithium augmentation, so we have emerging evidence that atypical antipsychotic medications can play an important role as adjunctive therapy for treatment-resistant MDD patients who have not had adequate benefit from our first or second choices of antidepressant monotherapy.”

Bipolar Depression: Findings from EMBOLDEN II

Focusing on treatment for bipolar depression, Dr. Lakshmi Yatham, Associate Professor of Psychiatry, University of British Columbia, Vancouver, stated here at the ECNP that although there is an overall paucity of treatments that can be proposed as evidenced-based therapy for bipolar patients, 5 large, double-blind trials with quetiapine provided enough patients to assess its efficacy in a bipolar setting.

In the EMBOLDEN II (Efficacy of Seroquel in Bipolar Depression) trial, both 300 and 600 mg/day were significantly more effective than placebo and the SSRI paroxetine at reducing symptoms of bipolar depression as assessed by changes in baseline MADRS total score. The superior effect of the atypical antipsychotic over placebo was observed at week 2 and lasted throughout the 8-week study. Fewer patients who continued with it in an extension phase relapsed compared with those switched to placebo, suggesting that the atypical antipsychotic is not only effective in treating acute bipolar depression but also in preventing depressive relapses in bipolar patients.

“Most guidelines do not talk about bipolar depression, which is a historically understudied indication, but our Canadian guidelines and, more recently, the World Biological Psychiatry guidelines do, and both suggest that quetiapine provides the best evidence of efficacy against bipolar II depression,” Dr. Yatham informed delegates. “In terms of combining quetiapine with something like lithium, that would be for patients who had been on lithium for prophylaxis, and if they had a breakthrough bipolar episode we might add quetiapine; the combination of quetiapine and lithium is quite safe and we do use it. There are also data suggesting that quetiapine and lithium in combination are more effective in preventing both depressive and manic relapses compared to lithium and placebo.”

The EMBOLDEN II study investigators noted that by demonstrating the effectiveness of quetiapine monotherapy over paroxetine and placebo, valuable new evidence now supports its use as a first-line treatment option for bipolar depression. The common practice of using antidepressants, often as monotherapy, to treat bipolar depressed patients appears to need re-examination in light of EMBOLDEN II.

Dr. Yatham remarked, “The pivotal questions about the other treatments are whether they really work or if there are problems with the design of the trials. Are the scales used to measure changes in depressive symptoms sensitive enough or are there other methodologic issues that prevent us from detecting the true efficacy of antidepressive agents?”

MDD Clinical Development Program

Noting that conventional antidepressants are successful in fewer than 50% of patients, Prof. Stuart Montgomery, Emeritus Professor of Medicine (retired), Imperial College School of Medicine, London, UK, reported here at the ECNP that the clinical development program for once-daily quetiapine XR in MDD patients demonstrates antidepressant efficacy in 80% of patients in acute monotherapy studies. He concurred that some trial designs might merit further investigation.

Prof. Montgomery stated that the robust design of the quetiapine XR clinical development program in MDD included elements considered important in determining and detecting antidepressant effects. They are enrolling patients with moderate-to-severe depression; entering patients with anxiety symptoms but excluding those with Axis I/Axis II comorbidities; and using various dosing strategies (including fixed dose) with multiple treatment arms, each comprising a large number of patients. It also employed different scales to assess eligibility and outcomes to potentially counter any inherent bias of the scales, avoid rater inflation, and included active controls for assay sensitivity. “It is possible that this more inclusive approach recruited patients more representative of individuals with severe MDD,” Prof. Montgomery told delegates.

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