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Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm |
Nolen W A, Bloemkolk D |
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Authors' objectives To discuss all controlled studies on the treatment of bipolar depression with mood stabilisers or antidepressants, with an emphasis on both their acute effect against depression as well as their risk to induce mania or hypomania.
Searching MEDLINE was searched from 1960 to 1999 (updated to February 2000) for literature; the search terms were reported. In addition, reference lists were examined and recent books of congress abstracts were searched.
Study selection Study designs of evaluations included in the reviewDouble-blind randomised controlled trials (RCTs), with or without a placebo group, were eligible.
Specific interventions included in the reviewStudies of mood stabilisers or antidepressants were eligible. To be included, studies were required to provide information about all used medication (including concurrent use of other mood stabilisers) and the dose and duration of the antidepressants used. The mood stabilisers used in the included studies were lithium, carbamazepine and lamotrigine; the antidepressants were imipramine, desipramine, paroxetine, fluoxetine, moclobemide, tranylcypromine and buproprion. In some of the studies of antidepressants, mood stabilisers (including lithium, carbamazepine, antipsychotic, and valproate) were used concurrently in some patients.
Participants included in the reviewStudies of patients with bipolar depression were eligible. Studies with a broader population (e.g. patients with major depressive episode) were eligible only if they presented results for participants with bipolar depression separately. The included studies comprised either a mixed population of unipolar depressed and bipolar depressed patients, or bipolar depressed patients only.
Outcomes assessed in the reviewStudies providing an operational definition of response criteria and specifying the number of drop-outs during the study, including switches into mania or hypomania, were eligible.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality The authors do not state that they assessed validity.
Data extraction The authors do not state how the data were extracted for the review, or how many of the reviewers performed the data extraction. The categories of data extracted were mood disorder, number of patients, antidepressant, mood stabiliser, dose, study duration, and results.
Methods of synthesis How were the studies combined?The results of the included studies were discussed in a narrative.
How were differences between studies investigated?Differences between the studies were discussed in the text of the review.
Results of the review Nine RCTs containing a total of 894 participants met the inclusion criteria.
One RCT of lithium versus placebo found that 80% (n=32) of patients with bipolar depression responded to lithium versus 33% (n=4) of those with unipolar depression. Of the 32 responding patients with bipolar depression, 38% (n=12) relapsed after switching to placebo. In one RCT patients received placebo before and after carbamazepine; 62% (n=15) of patients with bipolar depression responded versus 45% (n=5) of those with unipolar depression. In a placebo-controlled trial, 51% receiving high-dose lamotrigine (200 mg/day) responded versus 45% receiving the low dose (50 mg/day) and 36% on placebo. The difference was non significant.
In one study, 60% of patients receiving fluoxetine showed a response compared with 40% of those receiving imipramine and 17% of those receiving placebo. No significant differences in response were found between imipramine, paroxetine and placebo in a study in which all patients were using lithium.
In one study, 75% of patients on tranylcypromine responded compared with 36% on imipramine (p=0.02). No significant differences in response were found in two studies comparing imipramine with moclobemide (in one of which the majority of patients were using lithium, carbamazepine or an antipsychotic). One study found comparable antidepressant effects of desipramine compared with buproprion during an ongoing treatment with one of the mood stabilisers lithium, carbamazepine or valproate.
In two studies of lithium and carbamazepine monotherapy, no development of (hypo)mania was reported. A switch rate into (hypo)mania of 8% was found in the high-dose lamotrigine group of one study, compared with 3% in the low-dose group and 4.5% in the placebo group. The difference was not statistically significant.
The risk of inducing (hypo)mania was somewhat, but not statistically significantly, higher when imipramine and desipramine were used than when fluoxetine, paroxetine, moclobemide or buproprion were used.
Authors' conclusions Mood stabilisers are probably effective in the acute treatment of bipolar depression. However, the efficacy of lithium and carbamazepine has not been proven in formal placebo-controlled trials. Of the newer anticonvulsants, only lamotrigine has been found to be effective. The limited data suggest that the antidepressants are also effective in acute bipolar depression. Several of the antidepressants do not seem to differ from each other in terms of their antidepressant efficacy, with the exception of tranylcypromine, which was found to be more effective than imipramine. However, it is not known whether tranylcypromine is as effective when combined with a mood stabiliser. The antidepressants seem to differ from each other in their risk of inducing (hypo)mania, with imipramine and desipramine being associated with a higher switch rate than the other antidepressants. Tranylcypromine was also found to be associated with a relatively high switch rate.
CRD commentary The review had a clear aim and was supported by a priori inclusion criteria relating to the intervention, participants, outcomes and study design. The literature search was limited, as only one electronic database was searched and there was no attempt to identify unpublished literature. In addition, it appears that the included studies were limited to those in English only. Hence, it is possible that relevant studies were omitted from the review. It was not stated how many of the reviewers were involved in selecting the studies and extracting the data. Therefore, it is unclear to what extent the results may have been biased. The studies were also not assessed for validity.
It was appropriate that the studies were not quantitatively pooled due to the clinical heterogeneity. However, the narrative synthesis of the studies was poor, as the results of the studies tended to be discussed individually rather than combined in the narrative. In addition, the results for the control group were often not presented and the groups were not compared statistically. The authors' conclusions should be regarded with caution in light of the methodological limitations of this review.
Implications of the review for practice and research Practice: The authors state that in the acute treatment of bipolar depression, it is recommended to start with a mood stabiliser, and to add an antidepressant after 4 to 6 weeks in case of nonresponse. In more severe cases, an earlier start with the combination of a mood stabiliser and an antidepressant might be considered, and there is a place for tranylcypromine in refractory patients. In bipolar depressed patients who have responded to combined treatment with a mood stabiliser and an antidepressant, the antidepressant should be withdrawn gradually; if a depressive relapse occurs, the antidepressant should be restarted and the combination continued after response.
Research: The authors did not state any implications for further research.
Bibliographic details Nolen W A, Bloemkolk D. Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm. Neuropsychobiology 2000; 42(Supplement 1): 11-17 Indexing Status Subject indexing assigned by NLM MeSH Algorithms; Antidepressive Agents /therapeutic use; Antidepressive Agents, Tricyclic /therapeutic use; Antimanic Agents /therapeutic use; Bipolar Disorder /drug therapy; Depressive Disorder /drug therapy; Humans; Lithium /therapeutic use; Serotonin Uptake Inhibitors /therapeutic use AccessionNumber 12001003196 Date bibliographic record published 30/11/2003 Date abstract record published 30/11/2003 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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