Oxcarbazepine in the treatment of acute affective episodes in bipolar disorder: efficacy and acceptability
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1. To determine the efficacy of oxcarbazepine compared to placebo or an alternative drug:
1.1 in alleviating manic symptoms episodes of bipolar disorder.
1.2 in alleviating mixed affective symptoms in acute episodes of bipolar disorder.
1.3 in alleviating depressive symptoms in acute episodes of bipolar disorder.
2. To review the acceptability of treatment with oxcarbazepine to patients, measured by numbers and reasons for dropping out of trials, compliance, and by reference to patients' expressed views regarding treatment.
3. To investigate the adverse effects of oxcarbazepine treatment including the general prevalence of adverse effects. Specified unwanted effects will be studied.
4. To determine the overall mortality rates on oxcarbazepine treatment
Background
Bipolar affective disorder is a chronic disorder with a lifetime prevalence of 1 to 5% (Akiskal 2000). It is classically manifest as repeated manic, depressed or mixed episodes with complete inter‐episode recovery, but one third of patients suffer chronic symptoms, which affect their social and occupational development. Mood stabilisers are used in the treatment of bipolar disorder. Ideally, they should treat affective episodes of all types efficaciously and prevent their re‐occurrence when used in maintenance therapy.
Lithium is the mood stabiliser in longest use. However, the response to lithium treatment is often unsatisfactory (Bowden 1996). It has a narrow margin of safety and is often associated with adverse effects, even at therapeutic doses. It is thought to precipitate episode recurrence on withdrawal, making its use in the non‐compliant patient problematic. The anticonvulsants carbamazepine and valproate have become established as adjunctive and alternative treatments to lithium. Recent data on atypical antipsychotics has shown that they may have anti‐manic activity without displaying the extra pyramidal adverse effects associated with the typicals (Keck 2000). However, even with these advances, treatment resistance persists, especially in those with bipolar depression: new medications with mood stabilising properties are required.
Recently there has been interest in the mood stabilising properties of several new anticonvulsants. Oxcarbazepine is an anticonvulsant indicated for use as single agent therapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy and as adjunctive treatment in the treatment of partial seizures in children aged 4‐16 with epilepsy (Beydoun 2002) . Several studies have suggested efficacy of the drug in affective disorders (Emrich 1985, Muller 1984, Munoz 2002, Hummel 2002, Ghaemi 2002).
Oxcarbazepine is an analogue of carbamazepine. However it has a distinct and different profile of metabolism in the liver. It is rapidly converted to its active metabolite 10, 11 ‐ dihydro‐ 10‐ hydroxy carbamazepine (MHD). Both oxcarbazepine and its metabolite, MHD, do not induce major hepatic oxidative metabolism mechanisms and therefore they do not have many drug interactions unlike carbamazepine (Isojarvi 1994). At the drug receptor level, however, both oxcarbazepine, its MHD metabolite, and carbamazepine have a similar mechanism of action. They inhibit the influx of sodium inside nerve cells and also enhance opening of potassium channels which is known to reduce transmission of nerve impulses.
The most frequent adverse effects of oxcarbazepine include dizziness, sedation, and blurred vision (Dietrich 2001). Rash is less commonly reported with oxcarbazepine compared to carbamazepine; however 25‐30% of patients with hypersensitivity to carbamazepine are also hypersensitive to oxcarbazepine (Dietrich 2001). The potential for this molecule to induce other serious non‐dose related reactions associated with carbamazepine including agranulocytosis, hepatic reactions, and aplastic anaemia is considered to be lower (Dietrich 2001). However hyponatremia has been reported in a number of patients treated with oxcarbazepine and the maximum risk has been reported in the first 12 weeks of treatment (PDR 2001).
Anticonvulsants like sodium valproate and lamotrigine are now considered to be important options in the treatment of bipolar disorders (De Leon 2001). Newer agents like oxcarbazepine need to be evaluated for their possible role in acute bipolar affective episodes and in treatment resistant patients.
Objectives
1. To determine the efficacy of oxcarbazepine compared to placebo or an alternative drug:
1.1 in alleviating manic symptoms episodes of bipolar disorder.
1.2 in alleviating mixed affective symptoms in acute episodes of bipolar disorder.
1.3 in alleviating depressive symptoms in acute episodes of bipolar disorder.
2. To review the acceptability of treatment with oxcarbazepine to patients, measured by numbers and reasons for dropping out of trials, compliance, and by reference to patients' expressed views regarding treatment.
3. To investigate the adverse effects of oxcarbazepine treatment including the general prevalence of adverse effects. Specified unwanted effects will be studied.
4. To determine the overall mortality rates on oxcarbazepine treatment
Methods
Criteria for considering studies for this review
Types of studies
Prospective randomised and quasi‐randomised trials comparing oxcarbazepine in the treatment of acute affective episodes (manic, mixed affective or depressive episodes) with placebo or alternative drug treatment in bipolar affective disorder. It is anticipated that the number of studies employing strict criteria of randomisation will be few. Studies where cluster randomisation is used or where the randomisation procedure is unclear will also be included. However, sensitivity analysis will be employed to assess the effects of the inclusion of these trials.
Discontinuation trials, in which patients receive oxcarbazepine prior to randomisation (other than for short periods of stabilisation), will be analysed separately. We anticipate that some trials may combine acute treatment and maintenance phases, and where possible, we will separate these data for the purposes of this review.
Types of participants
Males and females of all ages with a diagnosis of bipolar disorder approximating to ICD‐10 Code F31* (WHO 1992) and/or DSM IV 296* (APA 1994). All subtypes of bipolar disorder (rapid cycling‐suffering from four or more affective episodes per year), types I and II and other) will be included; cyclothymia will be excluded. It is recognised that some trials may involve heterogenous groups of subjects: in particular, they may include schizo‐affective disorder and unipolar depressive disorder (diagnoses approximating to ICD‐10 F25 and DSM 295.70, and ICD‐10 F33 and DSM IV 296.3, respectively). Where possible, data from these studies will be separated into diagnostic groups. If necessary, the authors of the studies will be requested to provide original data. Where such separation is impossible, the studies will be included but a sensitivity analysis will be conducted to examine the effect of their inclusion. However, if we are unable to obtain a separation of such heterogenous data, we will extract information from these studies only if at least 80% of randomised patients had a bipolar diagnosis.
Patients with acute affective episodes will be included:
1.Patients with depressive episodes, with or without psychotic symptoms, approximating to ICD‐10 Codes F31.3‐31.5* and/or DSM IV 296.21‐4 and 296.31‐4*
2.Patients with a diagnosis of mixed affective disorder, with or without psychotic symptoms, approximating to ICD‐10 Code F31.6* and/or DSM IV Code 296.61‐4*
3.Patients with a diagnosis of hypomania or mania with or without psychotic symptoms approximating to ICD‐10 codes F30.0 and F31.0‐31.2* and/or DSM Code 296.40 or 296.41‐4*
* Trials with ICD‐9 and/or DSM III/IIIR diagnoses approximating to these codes will be included.
Types of interventions
Acute treatment will be defined as treatment instituted specifically to alleviate symptoms of an existing acute episode. Intervention parameters will include oxcarbazepine in the treatment of acute manic, mixed affective or depressive episodes in the context of bipolar disorder compared with:
1. placebo
2. alternative mood stabiliser treatment
3. combination mood stabiliser treatment
4. other drug treatments, e.g. neuroleptic medication
Types of outcome measures
For each type of episode a separate analysis will be conducted according to the criteria listed. All outcome measures will be evaluated by estimating changes from baseline to the end of study period.
1. Primary Outcome: Number of patients failing to respond to treatment by end of study period
Secondary Outcomes: For each type of affective episode the following outcome measures will be estimated
For manic episodes, efficacy of treatment will be measured by:
Requirement for hospital admission
Length of hospital admission
Time to cessation of additional treatment for manic symptoms
Scores in manic symptom rating scales
Scores in psychotic symptom scales.
For mixed affective episodes, efficacy of treatment will be measured by:
Requirement for hospital admission
Length of hospital admission
Time to cessation of additional treatment for mixed affective symptoms
Scores in symptom rating scales.
For depressive episodes, efficacy of treatment will be measured by:
Requirement for hospital admission
Length of hospital admission
Time to cessation of additional treatment for depressive symptoms
Scores in symptom rating scales.
2. Psychological social and occupational functioning as measured by:
Global impression of the clinician
Global impression of the subject, family or significant others.
3. Acceptability of oxcarbazepine treatment, as measured by:
Subjects dropping out of the treatment during the study period.
Subjects' reports of satisfaction or otherwise with treatment.
4. Adverse effects:
Subjects experiencing:
Troublesome adverse effects of any nature
Then specific adverse effects will be considered:
Dizziness
Diplopia
Somnolence
Fatigue
Nausea
Vomiting
Ataxia
Abnormal Vision
Abdominal pain
Tremor
Dyspepsia
Abnormal gait
Rare/serious events: will be reported in the text.
Haematological disturbances
Hyponatraemia
5. Mortality Rates:
Overall mortality rates during the study period
Mortality excluding suicide and verdicts of undetermined death
Mortality due to iatrogenic causes
Suicide and verdicts of undetermined death.
Search methods for identification of studies
See: CCDAN Collaborative Review Group search strategy
ELECTRONIC DATABASES:
The following terms will be used for oxcarbazepine in our database search: (oxcarbazepine, Trielptal, GP 47.680, Apydan)
The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR‐Studies) will be searched using the following search strategy;
Intervention = Oxcarbazepine.
The following databases will be searched using Cochrane Collaboration search algorithms, as given below, for trials relevant to the use of oxcarbazepine in bipolar disorder:
1. The Cochrane Controlled Clinical Trials Register (CCTR)
2. Medline (1966‐January 2004)
The following search strategy will be performed
1 randomized‐controlled‐trial.pt.
2 controlled clinical trial.pt.
3 randomized controlled trials.sh.
4 random allocation.sh.
5 double blind method.sh.
6 single blind method.sh.
7 clinical trial.pt.
8 exp Clinical trials/
9 (clin$ adj25 trial$).ti,ab.
10 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$ or
dummy$)).mp. [mp=title, abstract, cas registry/ec number word, mesh
subject heading]
11 placebos.sh.
12 placebo$.ti,ab.
13 random$.ti,ab.
14 research design.sh.
15 comparative study.sh.
16 exp evaluation studies/
17 follow up studies.sh.
18 prospective studies.sh.
19 (control$ or prospectiv$ or volunteer$).ti,ab.
20 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13
or 14 or 15 or 16 or 17 or 18 or 19
21 (animal not human).sh.
22 20 not 21
23 bipolar disorder.ti,ab
24 mania.ti,ab
25 unipolar mania. ti,ab
26 bipolar affective disorder. ti,ab
27 23 or 24 or 25 or 26
28 22 and 27
This will be combined with (oxcarbazepine, trileptal, apydan, GP 47.680)
Embase (1980‐January 2004)
1 Controlled study/
2 Clinical trial/
3 Major clinical study/
4 Randomized controlled trial/
5 Double blind procedure/
6 Clinical article/
7 random$.ti,ab,hw.
8 trial$.ti,ab,hw.
9 compar$.ti,ab,hw.
10 control$.ti,ab,hw.
11 study.ti,ab,hw.
12 follow$.ti,ab,hw.
13 clinic$.ti,ab,hw.
14 blind$.ti,ab,hw.
15 placebo$.ti,ab,hw.
16 doubl$.ti,ab,hw.
17 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
or 13 or 14 or 15 or 16
18 Animal/
19 Nonhuman/
20 18 or 19
21 Human/
22 20 and 21
23 20 not 22
24 17 not 23
25 oxcarbazepine.ti,ab,hw
26 trileptal. ti,ab,hw.
27 GP 47.680. ti,ab,hw
28 apydan. ti,ab,hw
29 25 or 26 or 27 or 28
30 29 and 24
31 bipolar dis$.ti,ab,hw
32 bipolar affective dis$.ti,ab,hw
33 mania.ti,ab,hw
34 unipolar mania.ti,ab,hw
35 30 and 34
PsycLit (1996‐January 2004)
1 random*
2 singl*
3 doubl*
4 tripl*
5 trebl*
6 blind*
7 mask*
8 (#2 or #3 or #4 or #5) near (#6 or #7)
9 crossover
10 cross‐over
11 versus
12 vs
13 #1 or #8 or #9 or #10 or #11 or #12
14 "oxcarbazepine" in DE
15 oxcarb*
16 trileptal
17 GP 47.680
18 apydan
19 oxcarb* or trileptal or GP 47.680 or apydan
20 bipolar*
21 affective disorder*
22 mania*
23 unipolar mania*
24 #20 or #21or #22 or #23
25 #19 or #24
Lilacs and Psyndex will be searched only for randomised controlled trials through the CCDANCTR.
REFERENCE CHECKING
The reference lists of all identified randomised controlled trials will be checked. Cross references from other published papers including open label studies, review articles and case note analysis will also be checked. Textbooks on affective disorders including Essential Psychopharmacology of Depression and Bipolar Disorder, New Oxford textbook of Psychiatry, and The American Psychiatric Publishing Textbook of Psychopharmacology will also be checked.
HAND SEARCHING
Journals or conference proceedings specifically relating to oxcarbazepine therapy in bipolar disorder will be hand searched. The following conference proceedings will be hand searched‐ American Psychiatric Association, CINP and the British Association of Psychopharmacology.
PERSONAL COMMUNICATION
The authors of significant papers over the last five years will be identified from authorship lists. They, and other experts in the field, will be contacted and asked of their knowledge of other studies, published or unpublished relevant to the review. Pharmaceutical companies marketing oxcarbazepine products will be requested to provide relevant published and unpublished data (see CCDAN group policy).
No language restriction will be applied within the limitations of the search tools.
Data collection and analysis
A) Selection of trials
Studies generated by the search strategies will be checked to ensure they meet the previously defined inclusion criteria by two reviewers. Any disagreements will be resolved by consensus discussions with a third member of the review team.
B) Quality assessment
Two reviewers will independently assess the methodological quality of the included studies. Quality will be assessed according to the Cochrane criteria for quality assessment (Alderson 2004). This pays particular attention to the adequacy of the randomisation procedure. On this basis, studies will be given a quality rating of A (adequate), B (unclear) and C (inadequate). If the raters disagree, the final rating will be made by consensus with the involvement, if necessary, of another member of the review group. In addition, other aspects of quality such as blinding and reporting of withdrawals and dropouts will be described in the text. Where inadequate details of randomisation and other characteristics of trials are provided, the authors will be contacted in order to obtain further information. Studies will be included for assessment if they have a quality rating of B or above.
C) Data Extraction
Two reviewers will independently extract data concerning participant characteristic, intervention details (including whether or not the study was of discontinuation design) and outcome measures from the included studies. Any disagreements will be resolved by consensus discussions with a third member of the review team.
Non‐concurrence in selection and quality assessment will be reported.
D) Data Analysis
Data will be entered into Review Manager 4.2.3 software by one reviewer.
For binary efficacy outcomes, a relative risk (with 95% confidence intervals) will be calculated using a fixed effects model. Relative risk ratios and NNT/NNH with 95% confidence intervals will also be calculated for any stastically significant findings. Heterogeneity between studies will be assessed using the chi squared test of heterogenity and also by visual inspection. Stastical significance value (p) of 0.1 will be used for this test. If significant heterogeneity is identified, sources will be investigated. Potential sources include the presence of schizoaffective and unipolar groups in the sample, variation in dose and duration of treatment, demographic factors and illness characteristics. Any other potential source of heterogenity which is apparent on examining the studies will also be included. Random effects models will be used to investigate the sensitivity of results to the choice of statistical method.
For continuously distributed outcome data, the results will be pooled as for binary outcome measures and heterogeneity assessed in the same way. The weighted mean difference (WMD) will be used if all the trials use the same assessment scale. However if the trials use different assessment scales, the standardised mean difference (SMD) will be calculated. If different assessment scales are used, then this potential source of heterogeneity will be assessed.
We will use intention‐to‐treat data when available. For binary efficacy outcomes and continuously distributed outcomes, ITT analysis will be performed using available case analysis and using imputation. The results arising from these two methods will be compared during sensitivity analysis. Where ITT analysis is not possible, end‐point data for trial completers will be used. When it appears that data are skewed, using recommended methods for identifying skewness from summary data (Altman 1996), they will be reported descriptively. A negative outcome will be assumed if subjects drop out of the study for any other reason than response to treatment. Non‐quantitative data will be presented descriptively. Outcomes concerning relapse/recurrence of affective disorder will be analysed excluding data from studies of discontinuation design. Data from these studies will be analysed separately, to assess the effects of oxcarbazepine discontinuation.
Sensitivity analyses will be performed excluding studies of lower methodological quality and trials of more than 50% non‐completers to assess the robustness of the results. Sub‐group analyses will be performed when appropriate to assess the outcomes of oxcarbazepine treatment of mixed affective episodes, affective disorder with psychotic features, schizo‐affective disorder and recurrent unipolar depression (Oxman 1995). Sub‐group analyses will also be performed to assess the effectiveness of oxcarbazepine treatment in previous mood stabiliser non‐responders.
Funnel plots will be used for determination of publication bias.
