Tiagabine 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 Tiagabine:
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.
1.4 on patients' general health and social functioning as measured by global clinical impression.
2. To review the acceptability of treatment with Tiagabine to patients, measured by numbers and reasons for dropping out of trials, adherence to treatment, and by reference to patients' expressed views regarding treatment.
3. To investigate the adverse effects of Tiagabine treatment including the general prevalence of adverse effects. Some of the adverse effects that have been reported are
dizziness, somnolence, fatigue, headache, tremor, irritability, difficulties in concentration, confusion, insomnia, nystagmus, depression, amnesia, speech difficulties, paraesthesias and incoordination (Leppik 1999). We will elicit the incidence of these adverse events in the review and also record other adverse events, if any, as reported by other authors.
4. To determine the overall mortality rates on Tiagabine treatment and also:
Mortality excluding suicide and verdicts of undetermined death.
Mortality due to iatrogenic causes.
Suicide and verdicts of undetermined death.
Background
Bipolar disorder is a common recurrent illness with high rates of chronicity. 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. It ranks second amongst mental illnesses in the causes of worldwide disability (Murray 1997). 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. It remains a first choice in the treatment of bipolar disorder. However, the response to lithium treatment is often unsatisfactory (Bowden 1996). It has a narrow therapeutic window and is often associated with side 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. 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 anti convulsants, Tiagabine is an anticonvulsant used in adjunctive treatment of focal and secondary generalised epilepsy. It (Genton 2001) is a lipophilic derivative of nicopetic acid which blocks the uptake reuptake of gamma‐aminobutyric acid through the inhibition of GAT 1‐25 transportation system (Suzdak 1995). The drug is completely absorbed, achieves peak serum concentrations in 1‐2 hours. Tiagabine is widely distributed and easily crosses the blood brain barrier. Patients with epilepsy appear to tolerate Tiagabine well (Sachdeo 1997).
Anticonvulsants like sodium valproate and lamotrigine have become important options in the treatment of Bipolar disorders (De Leon 2001). Newer agents like tiagabine need to evaluate in acute bipolar affective episodes, to explore and establish a variety of treatment options including those for treatment resistance.
Objectives
1. To determine the efficacy of Tiagabine:
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.
1.4 on patients' general health and social functioning as measured by global clinical impression.
2. To review the acceptability of treatment with Tiagabine to patients, measured by numbers and reasons for dropping out of trials, adherence to treatment, and by reference to patients' expressed views regarding treatment.
3. To investigate the adverse effects of Tiagabine treatment including the general prevalence of adverse effects. Some of the adverse effects that have been reported are
dizziness, somnolence, fatigue, headache, tremor, irritability, difficulties in concentration, confusion, insomnia, nystagmus, depression, amnesia, speech difficulties, paraesthesias and incoordination (Leppik 1999). We will elicit the incidence of these adverse events in the review and also record other adverse events, if any, as reported by other authors.
4. To determine the overall mortality rates on Tiagabine treatment and also:
Mortality excluding suicide and verdicts of undetermined death.
Mortality due to iatrogenic causes.
Suicide and verdicts of undetermined death.
Methods
Criteria for considering studies for this review
Types of studies
Randomised trials comparing Tiagabine in the treatment of acute affective episodes (manic, mixed affective or depressive episodes) with placebo or other drug treatment in bipolar disorder. Acute treatment will be defined as treatment instituted specifically to alleviate symptoms of an existing acute episode. Discontinuation trials, in which patients receive Tiagabine 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 corresponding to ICD 10 Code F31* (WHO 1992) and 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.
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 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 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 DSM Code 296.40 or 296.41‐4*
* Trials with ICD 9 and DSM III/IIIR diagnoses approximating to these codes will be included.
Types of interventions
Tiagabine 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 treatment, e.g. neuroleptic medication Where Tiagabine has been used as an adjunctive treatment in combination with another mood stabiliser, this will be considered separately.
Types of outcome measures
1.1.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.
Changes in manic symptom rating scales.
Changes 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.
Changes in symptom rating scales.
Changes in psychotic symptom 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.
Changes in symptom rating scales.
Changes in psychotic symptom scales.
2.General Health and Social Functioning, as measured by:
Global impression of the clinician.
Global impression of the subject, family or significant others.
3.Acceptability of Tiagabine 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 side effects of any nature will be recorded.
T5.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
ELECTRONIC DATABASES:
The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR‐Studies) will be searched using the following terms:
Intervention = Tiagabine
The following databases will be searched using Cochrane Collaboration search algorithms for trials and Tiagabine or Gabitril
The Cochrane Central Register of Controlled Trials (CENTRAL).
EMBASE (1980‐2003).
Medline (1966‐2003)
REFERENCE CHECKING.
The reference lists of all identified randomised controlled trials, other relevant papers and major English textbooks of affective
disorder will be checked.
HAND SEARCHING.
Any journals or conference proceedings specifically relating to Tiagabine therapy in bipolar disorder or unipolar depression will
be hand searched.
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 Tiagabine products will be requested to provide relevant published and unpublished data (see CCDAN group policy).
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. The reviewers will be blind to the authorship and source of the papers. Quality will be assessed according to the Cochrane criteria for quality assessment (Sackett 1997). 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.
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 Revman 4.2 software by one reviewer.
For binary efficacy outcomes, a pooled odds ratio and relative risk (with 95% confidence intervals) will be calculated using a fixed effects model. Heterogeneity between studies will be assessed using the Q statistic (DerSimonian 1986) and also by visual inspection. If significant heterogeneity is identified, sources will be investigated. Random effects models will be used to investigate the sensitivity of results to the choice of statistical method. For continuously distributed outcomes, the weighted mean difference or standardised mean difference will be calculated as appropriate.
We will use intention‐to‐treat data when available. Where this 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. 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 Tiagabine discontinuation.
Sensitivity analyses will be performed excluding studies of lower methodological quality to assess the robustness of the results. Sub‐group analyses will be performed when appropriate to assess the outcomes of Tiagabine 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 Tiagabine treatment in previous mood stabiliser non‐responders
