Tiagabine for acute affective episodes in bipolar disorder

Abstract

Background

Bipolar disorder is a common recurrent illness with high levels of chronicity. Treatment resistance persists despite the use of established medications, such as lithium and valproate. New medications are required for the treatment of refractory cases. Some open‐label reports have suggested that the anticonvulsant tiagabine may be efficacious in bipolar disorder. There is a need to clarify the evidence available, in the form of randomised controlled trials, for its use in the treatment of acute affective episodes in bipolar disorder.

Objectives

To review the evidence for the efficacy and acceptability of tiagabine in the treatment of acute mood episodes in bipolar disorder.

Search methods

In this update, we searched the Cochrane Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR‐Studies and CCDANCTR‐References) to October 2012. This register contains relevant randomised controlled trials from: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). We examined reference lists of relevant papers and major textbooks of affective disorder. We contacted authors, other experts in the field and pharmaceutical companies for knowledge of suitable published or unpublished trials. We handsearched specialist journals and conference proceedings.

Selection criteria

Randomised controlled trials, which compared tiagabine with placebo or with active agents in the treatment of any acute mood episodes in bipolar disorder in adults, male and female, aged 18 to 74 years.

Data collection and analysis

Two review authors performed data extraction and methodological quality assessment independently. For analysis, we planned to use risk ratio for binary efficacy outcomes and mean difference or standardised mean difference for continuously distributed outcomes.

Main results

In this updated review we found no studies which fulfilled the Cochrane criteria for randomised controlled trials.

Authors' conclusions

We found no randomised controlled trials of tiagabine in the treatment of acute episodes of bipolar disorder. However, there are reports that a number of patients suffered episodes of syncope or seizure. Further investigation of the efficacy and acceptability of tiagabine in the treatment of acute affective episodes of bipolar disorder should await the clarification of the nature of the reported episodes of syncope and seizure‐like activity and an examination of the level of risk involved.

Plain language summary

Tiagabine to treat acute affective episodes in bipolar disorder

This systematic review investigated the evidence base for the efficacy and acceptability of tiagabine compared to placebo and other pharmacological agents in the acute treatment of bipolar disorder. No randomised controlled trials were found. Currently, there is insufficient evidence on which to base any recommendations regarding the use of tiagabine in acute treatment of bipolar illness, either as a single treatment or as an additional treatment. A significant proportion of patients suffered episodes of syncope or seizure. There is a need for randomised controlled trials examining the efficacy and acceptability of tiagabine in the acute treatment of bipolar disorder, after the nature of these episodes has been clarified.

Background

Description of the condition

Bipolar disorder is a chronic disorder with a lifetime prevalence of 1% to 5% (Akiskal 2000) and carries with it significant morbidity, socioeconomic costs and risk of suicide. Classically, it is manifested in repeated manic, depressed or mixed mood episodes.

In the acute phase of the disorder it can present as:

1. an acute manic episode, where there are symptoms of elated mood, disinhibition and rapidity of thought;

2. an acute depressive episode, where mood is lowered and there are a range of changes in thoughts, emotions and bodily functions, such as sleep and appetite;

3. a mixed episode, where there are features of 1) and 2).

After the acute phase is over, by nature bipolar disorder tends to have repeated relapses. 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).

Description of the intervention

Mood stabilisers are used in the treatment of bipolar disorder. Ideally, they should treat affective episodes of all types efficaciously. 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. Data on atypical antipsychotics have also shown that they may have antimanic activity (Keck 2000; Rendell 2003). However, even with these advances, treatment resistance persists and hence newer interventions are constantly being sought and investigated. Recently, the application of a range of anticonvulsant agents in bipolar disorder has been explored. Tiagabine is an anticonvulsant used in adjunctive treatment of focal and secondary generalised epilepsy (Genton 2001) and may also have a role in the acute phase of bipolar disorder.

How the intervention might work

Putatively, tiagabine acts by blocking the uptake‐reuptake of the inhibitory neurotransmitter gamma‐aminobutyric acid (GABA) in the brain (Suzdak 1995). Patients with epilepsy appear to tolerate tiagabine well (Sachdeo 1997). However, the following adverse effects have been reported: dizziness, tiredness, somnolence, other signs of central nervous system suppression and incomplete seizure control (Leppik 1995). Interestingly, there are reports of a paradoxical association with non‐convulsive status epilepticus in a small number of patients with epilepsy (Balslev 2000; Kellinghaus 2001; Kellinghaus 2002; Knake 1999; Mangano 2003; Schapel 1996; Skodda 2001; Vinton 2005; Zhu 2002).

Why it is important to do this review

In view of the problem of treatment resistance in bipolar disorder, new medications which are both efficacious and well‐tolerated are required. There is some evidence of efficacy of tiagabine in maintenance treatment of bipolar disorder (Kauffman 1998; Schaffer 1999; Schaffer 2002) and we have previously reviewed and analysed the evidence in another Cochrane review (Vasudev 2011). There is a need to clarify the evidence for the use of tiagabine in the treatment of acute episodes of this disorder.

This is an update of a Cochrane review first published in 2006. That review did not find any randomised controlled trials and hence no conclusions could be drawn. This update explores publication of any new data which would inform the usage of tiagabine for the treatment of acute affective episodes in bipolar disorder.

Objectives

To assess the effects of tiagabine for the treatment of acute affective episodes of bipolar disorder.

The following were the outcome criteria.

1. To determine the efficacy of tiagabine compared to placebo, or an alternative drug, in acute treatment.

   1. In acute manic, depressive and mixed episodes of bipolar disorder.

   2. In rapid cycling disorder.

   3. On patients' general health and social functioning, as measured by clinician's global impression, by global impression of the participant, family members or significant others, and by employment and marital stability.

2. To review the acceptability of acute tiagabine treatment to patients, measured by: numbers of patients failing to complete studies; their reasons for dropping out; measures of compliance; and reference to the expressed views of patients regarding treatment.

3. To investigate the adverse effects of tiagabine treatment, including general prevalence of side effects. We also studied specific unwanted effects.

4. To determine overall mortality rates, if any, on tiagabine acute treatment.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing tiagabine in the treatment of acute mood episodes (manic, mixed mood or depressive episodes) with placebo or alternative drug treatments in bipolar disorder.

We included cluster‐randomised controlled trials, but were cautious of unit of analysis error issues (Higgins 2008a).

We excluded quasi‐randomised studies, such as those allocating participants by using alternate days of the week.

We excluded cross‐over studies where participants receive different treatments sequentially, because of potential carry‐over effects from all treatments.

Types of participants

Adults aged 18 to 74 years old with a diagnosis of bipolar disorder approximating to the International Classification of Diseases (ICD) 10 Code F31* (WHO 1992) and Diagnostic and Statistical Manual, Text Revision (DSM‐IV‐TR) 296* (APA 2000) were to be included. All subtypes of bipolar disorder (rapid cycling (suffering from four or more affective episodes per year), bipolar types I and II and other) were to be included; we excluded cyclothymia.

It was recognised that some trials may involve heterogenous groups of participants: in particular, they may include schizoaffective disorder and unipolar depressive disorder (diagnoses approximating to ICD 10 F25 and DSM 295.70, and ICD 10 F33 and DSM IV 296.2x/3x, respectively). Where possible, data from these studies were to be separated into diagnostic groups. If necessary, the authors of the studies were to be requested to provide original data. Where such separation was impossible, the studies were to be included only if at least 80% of randomised participants had a bipolar diagnosis. Furthermore, we would conduct a sensitivity analysis to examine the effect of their inclusion.

Participants with acute affective episodes were to be included:

1. Participants with depressive episodes, with or without psychotic symptoms, approximating to ICD 10 Codes F31.3‐31.5* and DSM IV 296.5x and 296.89.

2. Participants with a diagnosis of mixed affective disorder, with or without psychotic symptoms, approximating to ICD 10 Code F31.6* and DSM IV Code 296.6x*.

3. Participants 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 296.0xor 296.4x or 296.89*.

* Trials with ICD 9 and DSM III/IIIR diagnoses approximating to these codes would be included.

Types of interventions

Tiagabine as monotherapy or adjunctive therapy used as acute treatment in comparison with:

1. placebo;

2. alternative agent;

3. any form of combination treatment.

We applied no restrictions on dose, frequency or intensity.

We defined acute treatment as treatment instituted specifically to treat acute affective episodes of the illness. Any discontinuation trials in which the participant had received tiagabine prior to randomisation (other than for short periods of stabilisation) were to be analysed separately. Where trials combined acute treatment and maintenance phases, where possible, these data were to be analysed separately for the purpose of this review.

Where tiagabine had been used as an adjunctive treatment in combination with another pharmacological agent, this was to be considered separately.

Types of outcome measures

For each type of episode (acute manic, mixed affective or depressive) we planned to conduct a separate analysis according to the criteria listed. We planned to evaluate all outcome measures by estimating changes from baseline to the end of the study period.

Please see Table 1 for a description of the rating scales.

1. Description of ratings scales.

Name of rating scale	Details
Young Mania Rating Scale (YMRS) (Young 1978)	This scale has 11 items which are rated after a clinical interview. Irritability, speech rate and amount, content of thought and disruptive behaviour items are given extra weight in the total by being scored from 0 to 8, whereas the remaining items are scored from 0 to 4. Higher scores indicate more symptoms.
Clinical Global Impression ‐ Bipolar version (CGI‐BP) (Spearing 1997)	CGI‐BP is a 7‐point scoring system, with low scores showing decreased severity and overall improvement. Previous phases of illness are used as comparators for the assessed period.
Inventory of Depressive Symptomatology (IDS) (Rush 1996)	The IDS is a 28 or 30‐point self rated (IDS‐SR) and clinical‐rated (IDS‐CR) inventory of depressive symptoms. It is based on the DSM‐IV criteria of a major depressive episode. Each scale item is weighed equally from 0 to 3. The IDS is supposed to be more suitable for monitoring mood symptoms in an outpatient setting
Bech‐Rafaelsen Mania Rating Scale (BRMAS) (Bech 1978)	This is an 11‐item scoring scale: each symptom is measured from 0 to 4, increasing from 'not present' to 'severe'. The items included activity (motor and verbal), flight of thought, voice level, hostility/destructiveness, mood, self esteem, contact, sleep, sexual interest and work

Primary outcomes

The following were taken as primary outcomes.

1. The number of participants with mania responding to treatment evidenced by a 50% or greater fall in a mania rating scale (e.g. Young Mania Rating Scale, YMRS (Young 1978), Bech‐Rafaelsen Mania Rating Scale, BRMAS (Bech 1979)) by the end of the study period.

2. The number of depressed participants achieving a 50% or greater fall on a depression rating scale (e.g. Hamilton Depression Rating Scale, HDRS (Hamilton 1960)) for participants in other acute phases of bipolar disorder by the end of the study period.

3. The number of participants with mixed affective states achieving a 50% or greater fall on a depression or a mania rating scale.

Secondary outcomes

1. For each type of affective episode the following outcome measures were to be estimated.

For manic episodes, efficacy of treatment 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, e.g. Brief Psychiatric Rating Scale, BPRS (Overall 1962).

For mixed affective episodes, efficacy of treatment 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 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, e.g. Clinical Global Impression, CGI (Guy 1976);

• global impression of the participant, family or significant others.

3. Acceptability of tiagabine treatment, as measured by:

• participants dropping out of the treatment during the study period as a proportion of the total number of randomised patients (total drop out rate);

• participants dropping out due to inefficacy during the trial as a proportion of the total number of randomised patients (drop out rate due to inefficacy);

• participants' reports of satisfaction or otherwise with treatment.

4. Adverse effects

Participants experiencing:

• troublesome adverse effects of any nature

Then specific adverse effects were considered:

• dizziness

• somnolence

• depression

• confusion

• asthenia

• abdominal pain

• nausea

• anxiety

• tremor

Rare/serious events were to be reported in the text:

• seizures

• anaphylactic reactions

• suicidal ideation

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

CCDAN Specialised Register (CCDANCTR)

The Cochrane Depression, Anxiety and Neurosis Review Group (CCDAN) maintain two clinical trials registers at their editorial base in Bristol, UK, a references register and a studies‐based register. The CCDANCTR‐References Register contains over 29,000 reports of trials in depression, anxiety and neurosis. Approximately 60% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR‐Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU‐Psi coding manual. Please contact the CCDAN Trials Search Co‐ordinator for further details. Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950‐), EMBASE (1974‐) and PsycINFO (1967‐); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review‐specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization’s trials portal (ICTRP), drug companies, the handsearching of key journals, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses.

Details of CCDAN's generic search strategies can be found on the Group‘s website.

Electronic searches

CCDANCTR

1. We searched the CCDAN Specialised Register (CCDANCTR‐Studies and CCDANCTR‐References) to 23 October 2012, using the following free‐text terms: (tiagabine or gabitril).

We screened records for trials including patients with bipolar disorder.

2. We also searched CENTRAL (to Issue 10, October 2012) using the following terms:

#1 (tiagabine or gabitril):ti,ab,kw 
 #2 (affective NEAR disorder*):ti,ab,kw 
 #3 (bipolar or mania or manic or hypomani* or psychos* or psychotic or postpsychotic):ti,ab,kw 
 #4 (rapid NEXT cycling):ti,ab,kw 
 #5 (schizoaffective):ti,ab,kw 
 #6 (#1 AND ( #2 OR #3 OR #4 OR #5 ))

3. We searched the WHO trials portal (http://apps.who.int/trialsearch/Default.aspx) and ClinicalTrials.gov (http://www.clinicaltrials.gov/) (23 Oct 2012) for: (tiagabine or gabitril).

4. Earlier searches of MEDLINE, EMBASE and PsycLIT, conducted when the protocol was first published (2003), can be found in Appendix 1.

Searching other resources

Reference checking

We checked the reference lists of all identified randomised controlled trials, other relevant papers and major English textbooks of affective disorder.

Handsearching

We handsearched Comprehensive Psychiatry (2001 to 2011). We handsearched the annual conference proceedings of the American Psychiatric Association (2005 to 2011), the British Association of Psychopharmacology (2005 to 2011) and the Collegium Internationale Neuro‐Psychopharmacologicum (CINP; 2005 to 2011).

Personal communication

We identified the authors of significant papers over the last five years from authorship lists. We contacted them, and other experts in the field, and asked them of their knowledge of other studies, published or unpublished, relevant to the review. We asked pharmaceutical companies marketing tiagabine products to provide relevant published and unpublished data (see CCDAN group policy).

We applied no language restriction within the limitations of the search tools.

Data collection and analysis

Selection of studies

One review author (AV) scanned studies relating to tiagabine generated by the electronic search of the CCDANCTR. Than he individually read the abstracts of these studies to check if they fulfilled the following preliminary criteria for inclusion:

• randomised controlled trial;

• comparing tiagabine with a comparator;

• participants with bipolar disorder, of whatever type.

Such studies were highlighted for discussion with the second author (KM). After agreement, we ordered studies fulfilling the above criteria from the local medical library. Two review authors (AV and KM) then assessed all the full‐text articles from this preliminary list independently to see if they met the stricter inclusion criteria for the review. If the raters had disagreed the final ratings were to be made by consensus with the involvement (if necessary) of another member of the author team. We reported non‐congruence in selection of trials as percentage disagreement. We took care to avoid duplicating trials by inclusion of multiple papers reporting on the same trial; instead we linked these together as multiple references to the same trial.

Data extraction and management

Two review authors (AV and KM) independently were to extract data concerning participant characteristics (age, sex, bipolar diagnosis, comorbidity, severity of episode, treatment history, study setting), intervention details (intended dosage range, mean daily dosage actually prescribed, co‐intervention if any, tiagabine as investigational drug or as comparator drug, sponsorship) and outcome measures of interest from any included studies. Any disagreements were to be resolved by consensus discussions with a third member of the review team.

Non‐concurrence in selection and quality assessment was to be reported.

Assessment of risk of bias in included studies

In the original version of this review, we assessed methodological quality of included studies using the criteria sent out in the Cochrane Handbook for Systematic Reviews of Interventions (e.g. Higgins 2005); however, following the publication of the revised and expanded version (Higgins 2008a), we updated our methods accordingly.

Working independently, AV and KM were to assess the risk of bias of included studies using the tool described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008b).

We planned to assess the following items.

1. Sequence generation: was the allocation sequence adequately generated?

2. Allocation concealment: was allocation adequately concealed?

3. Blinding of participants, personnel and outcome assessors for each main outcome or class of outcomes: was knowledge of the allocated treatment adequately prevented during the study?

4. Incomplete outcome data for each main outcome or class of outcomes: were incomplete outcome data adequately addressed?

5. Selective outcome reporting: were reports of the study free of suggestion of selective outcome reporting?

6. Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?

We would have then included quotations from the text of included studies, to comment on how we assessed the risk of bias and judgements as follows.

• Low risk of bias

• Unclear risk of bias

• High risk of bias

If disputes were to arise as which judgement should be given, then resolution was to be achieved after consulting with the third review author (AHY).

Measures of treatment effect

For dichotomous outcomes we planned to calculate the odds ratio with 95% confidence limits. For continuously distributed outcome data we were to use the mean difference (MD) with 95% confidence limits if all the trials used the same assessment scale. However, if the trials use different assessment scales, the standardised mean difference (SMD) with 95% confidence limits would be calculated. If different assessment scales were used, then this potential source of heterogeneity was to be assessed.

Unit of analysis issues

Studies with cross‐over design

Trials with cross‐over design were excluded, hence unit of analysis issues did not arise because of this.

Cluster‐randomised studies

We identified no cluster‐randomised trials for this version of the review. If they are identified in a future update, we plan to use the generic inverse variance technique and the intraclass correlation coefficient to adjust for cluster effects, using RevMan 5 (RevMan 2011).

Studies with multiple treatment groups

No trials were found with multiple treatment groups. If they are identified in a future update, we plan to combine all relevant experimental intervention groups of the study into a single group.

Dealing with missing data

We planned to calculate study responders on an intention‐to‐treat (ITT) basis; this implies that drop‐outs were always included in the analysis. Where participants withdrew from the trial before the study endpoint, it was assumed that they would have experienced a negative outcome by the end of the trial (e.g. failure to respond to treatment). Where there were missing data and the method of 'last observation carried forward' (LOCF) had been used to do an ITT analysis, then we would use the LOCF data, with due consideration of the potential bias and uncertainty introduced. When dichotomous or continuous outcomes were not completely reported in the published literature, we would ask trial authors to supply the data on an individual basis. We would compare the results arising from these two methods during sensitivity analysis. Where ITT analysis was not possible, we were to use endpoint data for trial completers. When only the standard error (SE) or t‐statistics or P values were reported, we would impute standard deviations (SDs) for changes from baseline as described previously (Abrams 2005).

Assessment of heterogeneity

Heterogeneity between studies was to be assessed using the Chi² test of heterogeneity and also by visual inspection of the forest plots as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008a). A statistical significance value (P) of 0.1 was to be used for this test. If significant heterogeneity was to be identified, we would have investigated sources. Potential sources include the presence of schizoaffective and unipolar groups in the study sample, variation in dose and duration of treatment, demographic factors and illness characteristics. Any other potential source of heterogeneity which was apparent on examining the studies would also be included. We also planned to calculate the I² statistic, an estimate of inconsistency and measured by the percentage of variability in effect estimates that is due to heterogeneity rather than sampling error (chance), as suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008a).

Assessment of reporting biases

Funnel plots were to be used to determine publication bias. These would only be used when there were more than 10 included studies and even then we would interpret them with caution as they are only indicative of publication bias (Higgins 2008a). Forest plot assessment of reporting bias can be used for estimating publication bias but as there were no included studies, it was not considered.

Data synthesis

Data were to be entered into Review Manager 5 by one review author (AV).

The primary analysis was to be carried out with a random‐effects model using odds ratios (OR), which had the highest generalisability in our empirical examination of summary effect measures for meta‐analyses (Furukawa 2002). The robustness of this summary measure was to be routinely examined by checking the fixed‐effect model OR and the random‐effects model risk ratio (RR). Material differences between the models were to be reported. Fixed‐effect analyses were to be undertaken routinely for the continuous outcomes as well, to investigate the effect of the choice of method on the estimates. Material differences between the models were to be reported.

When it appeared that the data were skewed, using recommended methods for identifying skewness from summary data (Altman 1996), they were to be reported descriptively. A negative outcome was to be assumed if participants dropped out of the study for any other reason than response to treatment. Non‐quantitative data were to be presented descriptively. Outcomes concerning relapse/recurrence of affective disorder were to be analysed excluding data from studies of discontinuation design. Data from these studies were to be analysed separately, to assess the effects of tiagabine discontinuation.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008a), were to be performed as defined a priori to assess the outcomes of tiagabine treatment for:

1. mixed affective episodes;

2. affective disorder with psychotic features;

3. schizoaffective disorder;

4. rapid cycling disorder;

5. recurrent unipolar depression.

Where such separation was impossible, the studies were to be included but a sensitivity analysis conducted to examine the effect of their inclusion on the results. If such separation of heterogenous group data proved impossible, we planned to extract information from these studies only if at least 80% of randomised participants had a diagnosis of bipolar disorder.

Subgroup analyses were also to be performed to assess the effectiveness of tiagabine treatment in previous mood stabiliser non‐responders.

Sensitivity analysis

Sensitivity analyses were to be performed for the following:

• excluding trials at high risk of bias (assessed as 'High' or 'Unclear' by the review authors (AV and KM) for allocation concealment);

• excluding trials with more than 50% non‐completers;

• excluding trials where results have been reported using LOCF;

• analysis based on available cases rather than ITT;

• excluding studies where additional diagnoses of mixed affective episodes, affective disorder with psychotic features, schizoaffective disorder, rapid cycling disorder and recurrent unipolar disorder were recorded.

Results

Description of studies

We found two studies examining tiagabine in the treatment of acute episodes of bipolar disorder and three studies of maintenance treatment which included accounts of a phase of treatment for an acute episode. Please see Characteristics of excluded studies. We found no randomised controlled trials comparing tiagabine to an alternative agent; therefore no study met our criteria for inclusion in the review. We received no reports of ongoing studies of tiagabine in bipolar disorder from a number of experts that we approached. We did not find any additional ongoing studies from the handsearches of conference proceedings. No studies await further assessment. The presence of publication bias was not examined in this systematic review because there were no trials to allow meaningful formal assessment using funnel plots.

Included studies

No studies were included in the meta‐analysis.

Excluded studies

See Characteristics of excluded studies. Grunze 1999 conducted an open‐label study in eight participants where tiagabine was offered either as monotherapy or adjunctive to current mood stabiliser in acute mania. Tiagabine seemed to be more effective in illness of moderate severity. However, new‐onset seizures were noted in one patient who was already on an antiepileptic. Suppes 2002 conducted an open‐label adjunctive study in 13 participants with either hypomania or depression. Some improvement was noted in depressive symptoms but not in hypomania. No ITT analysis was carried out for four of the patients who dropped out due to adverse events. Of note was an episode of unresponsiveness in one patient which got better after stopping treatment.

Schaffer 1999 describes an open‐label adjunctive study of maintenance administration in 22 participants having mixed episodes, hypomania and mania. Thirty‐six per cent of participants responded on the efficacy outcome measures. However, 59% of the participants withdrew due to side effects (see details in Characteristics of excluded studies).

Kauffman 1998 and Schaffer 2002 describe results of tiagabine administration in two participants who received this agent in a maintenance fashion but there is some description of acute phase of the treatment (see Characteristics of excluded studies).

Risk of bias in included studies

No studies met the inclusion criteria for this review.

Allocation

No studies met the inclusion criteria for this review.

Blinding

No studies met the inclusion criteria for this review.

Incomplete outcome data

No studies met the inclusion criteria for this review.

Selective reporting

No studies met the inclusion criteria for this review.

Other potential sources of bias

No studies met the inclusion criteria for this review.

Effects of interventions

As we found no randomised controlled trials, no data were available for meta‐analysis.

Discussion

Over the six years since our last review, there have been no new published or unpublished randomised controlled trials (RCTs) of tiagabine in acute therapy of bipolar disorder. Though the reason for the lack of these data is unknown, it could be that scientists and clinicians have been missing out testing this particular GABAergic agent. This is confirmed by the lack of any ongoing studies as evidenced by our handsearches as well as further correspondence with a number of key opinion leaders. Indeed a frequently used agent in bipolar disorder, valproate, mediates its activity via the GABAergic system and has been found to be safe and efficacious (Macritchie 2003). Newer studies continue to implicate the GABA system in bipolar disorder (Fatemi 2011); good‐quality, prospective, randomised controlled trials of tiagabine in the acute treatment of bipolar disorder are needed.

The presence of new onset syncope/ seizure like activity potentially induced by this anti‐epileptic during the treatment of acute bipolar disorder remains of concern. This needs to be further investigated.

Summary of main results

This systematic review did not find any randomised controlled trials examining the efficacy and acceptability of tiagabine treatment for the prevention of affective relapses in the acute treatment of bipolar disorder. The three open‐label studies mentioned above found minimal efficacy of this agent. Patients suffering from depressive illness seemed to benefit more, however, compared to those with hypomanic illness. Three patients were reported to have suffered syncope or possible absence/generalised seizures.

There are a number of reports of tiagabine in association with non‐convulsive status epilepticus (Balslev 2000; Kellinghaus 2001; Kellinghaus 2002; Knake 1999; Mangano 2003; Schapel 1996; Skodda 2001; Vinton 2005; Zhu 2002). A MEDLINE search found nine published articles documenting this side effect in at least 17 epileptic patients. All age groups were affected. The effect was not related to dose. Non‐convulsive status epilepticus has been defined by the presence of typical delta wave activity with intermingled spikes on EEG, coupled with unresponsiveness clinically (Vinton 2005). Most patients appeared to improve following the reduction or withdrawal of tiagabine and/or addition of a benzodiazepine.

Overall completeness and applicability of evidence

There were no studies which met the inclusion criteria; it is difficult to comment on the applicability of the results of the review.

Quality of the evidence

This review had broad inclusion criteria, hence it was expected that the external validity of the findings would be high. However, as there were no RCTs which we identified, the actual validity cannot be commented upon.

Potential biases in the review process

We made attempts to procure all studies that would meet the inclusion criteria of the review. Hence potential for study selection bias was relatively low.

Agreements and disagreements with other studies or reviews

As far as we are aware, there are no other published systematic reviews of the usage of this agent for this condition at the moment, therefore we cannot comment on level of agreement.

Authors' conclusions

Implications for practice.

There is no published evidence from randomised controlled trials on which to base any recommendations regarding the use of tiagabine in any phase of acute bipolar illness, either as monotherapy or as an adjunctive treatment. We have identified a signal that there may be a problem with syncope/seizure‐like activity in some patients. It is unclear whether these episodes represent the same clinical phenomenon. Further, most of these incidents occurred in patients who were in receipt of other psychotropic and/or anticonvulsant agents, raising the possibility of drug interaction. We are unable to provide any definitive information regarding the estimation of risk. Given this concern and the absence of evidence of benefit, at this time, tiagabine cannot be recommended for acute episodes of bipolar disorder.

Implications for research.

Further investigation of the efficacy and acceptability of tiagabine in the treatment of acute affective episodes of bipolar disorder should await the clarification of the nature of the reported episodes of syncope and seizure‐like activity and an examination of the level of risk involved.

What's new

Date	Event	Description
10 May 2012	New citation required but conclusions have not changed	Methodology updated.
10 May 2012	New search has been performed	Searches updated and published note added.

History

Protocol first published: Issue 1, 2003
 Review first published: Issue 3, 2006

Date	Event	Description
5 November 2008	Amended	Converted to new review format.
24 May 2006	New citation required and conclusions have changed	Substantive amendment.

Notes

This review is up to date as of October 2012. As there is no evidence of ongoing trials in this area, unless specifically requested, this review is not scheduled for another update until 2017.

Appendices

Appendix 1. Previous search strategies to 2003 (MEDLINE, EMBASE, PsycLIT)

Search strategy: MEDLINE (1950 to 2003)
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 trial/
9	(clin$ adj25 trial$).ti,ab.
10	((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$ or dummy$)).mp.
11	placebos.sh.
12	placebo$.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	or/1‐19
21	exp animals/ not humans.sh.
22	20 not 21
23	(tiagabine or gabitril).mp.
24	22 and 23

Search strategy: EMBASE (1980 to 2003)
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$.ti,ab,hw.
17	or/1‐16
18	Animal/
19	Nonhuman/
20	18 or 19
21	Human/
22	20 and 21
23	20 not 22
24	17 not 23
25	tiagabine. ti,ab,hw.
26	gabitril. ti,ab,hw.
27	25 or 26
28	27 and 24
29	bipolar dis$.ti,ab,hw.
30	bipolar affective dis$.ti,ab,hw.
31	mania.ti,ab,hw.
32	unipolar mania.ti,ab,hw.
33	29 or 30 or 31 or 32
34	28 and 33

Search strategy: PsycLIT (now PsycINFO) to 2003
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	tiagab* or gabitril
15	#13 and #14

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Grunze 1999	Open‐label study 8 inpatients suffering from an acute manic episode of bipolar disorder received tiagabine either as monotherapy (2 patients) or as adjunctive therapy (6 patients) Dosage: initial dose of 20 mg a day increasing to a maximum dose of 40 mg a day Duration: 4 days Outcome criteria: change in mania scores on the Bech‐Rafaelsen Mania Rating Scale (BRMAS) (Bech 1978) Results: there was a decrease in BRMAS scores at the end of the study at day 14 in all of the patients, however none achieved statistical significance. Patients whose illness was of moderate severity (baseline score < 30) at the beginning of the study seemed to do better than those with severe illness (baseline score > 30). Serious adverse effects occurred in 2 patients. One patient had a generalised tonic clonic seizure after receiving 30 mg a day of tiagabine for 3 days. This patient had been receiving concomitant sodium valproate at a dose of 2500 mg a day. Another patient experienced severe nausea and vomiting after increasing the drug dosage from 30 to 40 mg a day. Nausea was reversible after discontinuation of the drug. There was no reported incidence of mortality during the trial.
Kauffman 1998	Authors reported 2 cases of bipolar disorder treated with tiagabine augmentation in an open‐label fashion at a dose of 4 to 12 mg/day in addition to other mood stabilisers Mood state was not measured by any objective scale Adverse events were not mentioned
Schaffer 1999	Case series of 22 adult patients suffering from refractory bipolar disorder Tiagabine was added open‐label to previous medication at a dose of 1 mg/day. Dosage was increased by up to 1 mg per week in a maintenance fashion. No exclusion criteria were applied. Patients had been on multiple other medications, details of which were not described. A mean dose of 4.1 mg (2.2 SD) of tiagabine was used. A priori positive response to tiagabine was measured on the Clinical Global Impression ‐ Bipolar version (CGI‐BP) (Spearing 1997). 8 of the 22 patients (36%) responded to tiagabine. All of the 14 non‐responders withdrew from the treatment; 13 withdrew because of unacceptable adverse effects and one due to poor compliance. Adverse effects leading to discontinuation included overactivation (5 patients), oversedation (4 patients), cognitive impairment (2 patients) and headaches (2 patients). One patient with epilepsy suffered a recurrence of absence seizures which had previously been controlled with gabapentin. All side effects were resolved within 1 to 2 days of tiagabine discontinuation. The report did not mention the methods used for assessment of adverse effects, including any laboratory investigations or subjective adverse effect scores. There was no reported incidence of mortality during the trial
Schaffer 2002	Authors describe 2 cases of tiagabine augmentation in patients with poorly controlled bipolar disorder in an open‐label fashion at a dose of 3 to 4 mg/day No objective scale was used to monitor mood state Adverse events were not mentioned
Suppes 2002	Open‐label study 17 patients suffering from bipolar disorder (type 1 and 2); results from 13 finally included. 6 patients were hypomanic and 7 were depressed. Tiagabine used as adjunctive therapy. Dosage: 4 mg a day with gradual increases of 4 mg a week as tolerated Duration: the end of the evaluation period was taken as the time at which new medication was required or existing (non‐trial) medication increased. The mean duration of treatment was 38 days. Outcome criteria: the Young Mania Rating Scale (YMRS) (Young 1978), Inventory of Depressive Symptomatology (IDS) (Rush 1996) and the Clinical Global Impression for Bipolar Disorder (CGI‐BP) (Spearing 1997) Results: on the CGI‐BP 3 patients were 'much or very much improved' while 10 were 'minimally improved, no change or worse'. The YMRS and IDS sores showed that there was some improvement in patients presenting with depression; however in hypomania there was no significant difference between the baseline and final scores 4 patients were excluded from analysis because of early discontinuation within the first week; 2 stopped due to side effects (nausea in one and decreased libido in the other); 2 discontinued because of apparent worsening of mood symptoms (not necessarily related to tiagabine) Of the patients whose response could be evaluated: 3 were discontinued from tiagabine administration due to significant adverse events; one of these had loss of consciousness and was incontinent of bladder and bowel. The event was unwitnessed. This patient had been on other anticonvulsant medication for his bipolar illness (divalproex, topiramate and gabapentin). On discontinuation of tiagabine the adverse effects abated. In another patient an episode of unresponsiveness, disorientation and 'shaking' was noted 4 months after initiation of tiagabine. This patient was on thioridazine, fluoxetine, alprazolam and zolpidem as well at the time of the adverse event. Discontinuing tiagabine again led to abatement of symptoms. In another patient a 'fainting spell' was noted with unresponsiveness, disorientation and unsteady gait. There was no loss of consciousness. Symptoms cleared after few hours of supportive treatment and oxygen therapy. Tiagabine was discontinued and the symptoms did not reoccur.

SD: standard deviation

Differences between protocol and review

We have updated the Methods section to meet the standards required by the 2008 Cochrane Handbook for Systematic Reviews of Interventions. These include changing the objectives into Cochrane format; we have provided more detail on study inclusion criteria (particularly participants, where an age range has now been introduced); we have separated the outcomes into primary and secondary; and the assessment of risk of bias is now performed using the Cochrane 'Risk of bias' tool.

Contributions of authors

Dr A Vasudev: performed the literature search, selection of trials, correspondence with key authors and opinion leaders, co‐wrote the protocol and drafted the review. 
 Dr KAN MacRitchie: selection of trials, drafted the review. 
 Dr NSK Rao: drafted the review. 
 Prof AH Young: drafted the review and supervised work. 
 Prof JR Geddes: drafted the review.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Stanley Medical Research Institute, USA.

Declarations of interest

None of the review authors are employees of or have shares in a pharmaceutical company. Professors Vasudev and Young and Dr Macritchie have spoken at meetings and attended conferences sponsored by various pharmaceutical companies and have participated in trials sponsored by pharmaceutical companies. JRG currently receives research funding from the UK Medical Research Council, the UK Economic and Social Research Council, the National Institute for Health Research, and the Stanley Medical Research Institute. He was expert witness for Dr Reddy's Laboratories and is Chief Investigator on the CEQUEL trial to which GlaxoSmithKline have contributed and supplied investigational drugs and placebo. Dr Karine Macritchie has worked on a project supported by an award NS‐EU‐166 from the Translational Medicine Research Collaboration. This consortium comprises the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow and Clyde), Scottish Enterprise and Pfizer (formerly Wyeth). She has also received funding for travel, accommodation and conference expenses from AstraZeneca. In the last two years Assistant Professor Vasudev has received financial remuneration for advice to Lundbeck.

New search for studies and content updated (no change to conclusions)