Focus
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New strategies for managing bipolar depression have been presented in recent publications and at a recent scientific meeting. Gary S. Sachs, M.D., principal investigator for the national Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, discussed challenges of treating bipolar depression in the newly published Review of Psychiatry, volume 24: Advances in Treatment of Bipolar Disorder (American Psychiatric Publishing, Inc., 2005). In his chapter, Dr. Sachs explained that challenges in weighing treatment options include assessing studies according to levels of evidence, for which there are some general standards, and sorting out discrepancies in basic terminology, such as what qualifies as a "mood stabilizer" or an "antidepressant." Dr. Sachs then reviewed the evidence for currently available treatments for bipolar depression. Although few randomized controlled studies of standard antidepressants have been conducted in patients with bipolar depression, this class of drugs is still the most widely prescribed. Unfortunately, these agents, especially tricyclic antidepressants, are thought to be more associated with a treatment-emergent affective switch than other types of treatments. Other agents, such as lamotrigine and atypical antipsychotics, have been shown to ameliorate acute depression and reduce abnormal mood elevation (acute and/or prophylactic activity). Agents with such "bimodal" activity represent attractive new treatment options for patients with bipolar depression. However, evidence for the efficacy and safety of novel therapies such as stimulants, phototherapy, omega-3 fatty acids, transcranial magnetic stimulation, and sleep deprivation remains unconvincing or is totally without experimental support. The STEP-BD bipolar depression treatment pathway, as explained by Dr. Sachs, is based on the best available evidence. It defines 14 clinical decision points that move the patient and physician through assessment, reasonable choice of treatment regimen, and initiation of treatment to a therapeutic endpoint–full response, intolerance, or nonresponse. Dr. Sachs stressed the importance of carefully choosing an initial treatment, pointing out that an agent with bimodal activity, such as lamotrigine, lithium, valproate, quetiapine, or olanzapine, can be effective and lessen the risk of a treatment-emergent affective switch when given alone or in combination with another agent. Several guidelines suggest no standard antidepressant should be prescribed without coadministration of one of these agents. Dr. Sachs concluded that, based on the evidence, lamotrigine, olanzapine combined with fluoxetine, olanzapine, and quetiapine should be considered first-line treatments for patients with bipolar depression. In a scientific symposium at the 2005 annual meeting of the American Psychiatric Association (APA), Dr. Sachs reported more details from STEP-BD regarding the use of standard antidepressants to treat bipolar depression (Symposium 9). Patients who sought treatment for bipolar depression but who did not want to enter the randomized portion of the study were followed in an open fashion. Among those who received adjunctive antidepressants, low recovery rates were reported, implying little benefit of adjunctive antidepressant treatment. In a scientific session at the APA, Gao discussed the role of typical and atypical antipsychotics in the treatment of bipolar depression (Scientific and Clinical Report Session 32). After reviewing the published literature, including 21 randomized trials and 12 nonrandomized prospective trials, Gao concluded that olanzapine and quetiapine monotherapy are effective for the acute treatment of bipolar depression. Both were clearly superior to placebo in alleviating depressive symptoms. Quetiapine had a large acute effect on depression, whereas olanzapine was more effective in the treatment of acute mania than acute depression. [top]
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In addition, several new research posters were presented that increase the understanding of bipolar depression and its treatment. Corya et al. reported results of a 24-week, open-label study of olanzapine-fluoxetine combination (OFC) and olanzapine monotherapy in patients with bipolar depression (NR366). Patients (N = 376) who completed an acute trial but who had not achieved remission received olanzapine monotherapy for 1 week and were then given the option of switching to OFC. Patients could switch to OFC or back to olanzapine monotherapy at any later point in the trial as well. Montgomery-Asberg Depression Rating Scale (MADRS) scores decreased significantly in all 3 treatment groups (OFC, olanzapine only, and switched), signifying response. The majority of patients from each group were considered to have achieved remission during this uncontrolled open extension. Treatment-emergent mania was low, at 5.9%. Bentley and colleagues investigated whether lamotrigine is more effective as monotherapy or adjunctive therapy in patients with bipolar depression (NR306). Patients with bipolar I disorder who were experiencing an acute depressive episode were enrolled in a lamotrigine maintenance therapy trial. During the 8- to 16-week open-label preliminary phase, 897 patients were assessed for response to treatment: 161 were receiving lamotrigine only, and 736 were receiving lamotrigine adjunctive to another treatment (usually an antidepressant). Both groups of patients experienced a significant (p < .05) decrease in depressive symptoms as measured by the Hamilton Rating Scale for Depression. Cookson and coworkers presented results from an 8-week study of quetiapine treatment of bipolar depression (NR300). Five hundred forty-two patients with bipolar I or II disorder who were experiencing a moderate to severe depressive episode were randomly assigned to treatment with 300 mg/day of quetiapine, 600 mg/day of quetiapine, or placebo. The investigators compared mean time to response and mean time to remission based on MADRS scores. Both were significantly (p < .001) shorter in both quetiapine groups compared with placebo. Mean time to response was 27.44 days with 300 mg/day of quetiapine, 25.50 days with 600 mg/day of quetiapine, and 37.05 days with placebo. Mean time to remission was 33.22 days with 300 mg/day of quetiapine, 30.92 days with 600 mg/day of quetiapine, and 41.24 days with placebo. Quetiapine was generally well tolerated. The authors also calculated that the number needed to treat (NNT) to determine efficacy of quetiapine was 5; a low NNT indicates superior efficacy. Dr. Sachs stressed the importance of these findings. There has been an impressive increase in our fund of high-quality evidence pertinent to bipolar depression. There are now 4 treatments that have been found better than placebo in adequately powered double-blind placebo-controlled studies: lamotrigine, quetiapine, olanzapine, and the combination of olanzapine and fluoxetine. In contrast, there remains little compelling evidence supporting the use of standard antidepressant medications. In fact, recently reported randomized data from the Stanley Foundation found standard antidepressants offered rather modest effectiveness when efficacy ratings were adjusted down to reflect treatment-emergent abnormal mood elevation (Bipolar Disord 2003;5:396-406). New treatment guidelines (e.g., APA, Texas Implementation of Medication Algorithms, and others) have already factored these data into their recommendations. This progress is welcome and exciting. Given the prevalence and disability associated with bipolar depression, a steady stream of new data is needed to further clarify the role of these medications and the older standard antidepressants.
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Drug names: lamotrigine (Lamictal), lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa), olanzapine/fluoxetine combination (Symbyax), quetiapine (Seroquel). Disclosure of off-label usage: The author has determined that, to the best of his knowledge, lamotrigine, lithium, olanzapine, and quetiapine are not approved by the U.S. Food and Drug Administration for the treatment of bipolar depression. Supported by an educational grant from GlaxoSmithKline.
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