Lamotrigine in the maintenance treatment of bipolar disorder

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine efficacy and safety of lamotrigine for the maintenance treatment of manic, depressive, and mixed episodes of bipolar disorder.

Background

Description of the condition

Bipolar disorder is a chronic mental disorder with repetitive cycles of mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health‐related quality of life (de Hert 2011). It is described by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) tool as a type of mental health condition that leads to extreme fluctuation in a person's mood, energy, and ability to function (American Psychiatric Association 2013). Bipolar disorder was the 46th greatest causes of disability‐adjusted life years (DALYs) in the world, placing it ahead of Alzheimer's disease and other dementias among the 291 disorders included in the Global Burden of Disease Study 2010 (Murray 2012), and it has a worldwide prevalence of 2.4% (Merikangas 2011). Bipolar disorder affects approximately 60 million people worldwide (WHO 2019a). The risk of suicide is higher in people with bipolar disorder than those with other mental disorders (Nordentoft 2011). The estimated rate of death by suicide was 0.2 people per year to 0.4 people per year among people with bipolar disorder (Sondergard 2008), and one‐year recurrence rate was 26.3% (Vazquez 2015). Therefore, in addition to treating recurrent mania/hypomania and depressive episodes, effective management of bipolar disorder after acute treatment of mood episodes using long‐term continuation therapy is warranted in order to minimize the risk of relapse or recurrence (Calabrese 2006).

Description of the intervention

For many years, lithium has been the standard treatment of bipolar disorder with acute mood episodes, polarity change prevention, prophylactic treatment, and suicide prevention (Geddes 2010; Smith 2007; Yildiz 2011). However, questions were raised over the potential overestimation of the effectiveness of lithium and the frequency of use of lithium for bipolar disorder is decreasing (Blanco 2002; Lyall 2019). Furthermore, lithium has been associated with congenital malformations during pregnancy for both the mother and the fetus (Poels 2018). It has been reported that rates of recurrence after lithium discontinuation sharply increased postpartum (Viguera 2000). Sodium valproate and carbamazepine, both antiepileptic drugs, are effective for the management of the bipolar mania and acute symptoms (Bowden 2005; Greil 1998); however, they are relatively less effective against depression of maintenance phase and depression of bipolar disorder (Ng 2007). Atypical antipsychotics including olanzapine (Berk 1999), quetiapine (Calabrese 2005; Ketter 2007), aripiprazole (Keck 2003), and risperidone (Segal 1998) have also demonstrated efficacy in the treatment of mania. For new anticonvulsants such as gabapentin (Vieta 2006), topiramate (Pigott 2016), zonisamide (Dauphinais 2011), and levetiracetam (Kaufman 2004), sufficient efficacy has not been demonstrated for bipolar disorder. Thus, there remains a need to identify additional pharmacological agents with sufficient and up‐to‐date evidence to demonstrate their effectiveness in preventing and managing relapse of bipolar disorder.

Lamotrigine is approved for the maintenance treatment of adults with bipolar disorder. Lamotrigine is indicated for use in numerous clinical guidelines as a first‐line pharmacological agent in the treatment of bipolar depression (Nivoli 2011). Lamotrigine is licensed by the US Food and Drug Administration (FDA) for the prevention of relapses in people with bipolar disorder. Although the evidence base regarding long‐term efficacy of lamotrigine is reasonably robust, five pivotal trials conducted in acute phase therapy reported relatively neutral findings and they found no statistically significant benefits (Calabrese 2008). Previous studies found that lamotrigine could be a viable and effective treatment modality for the maintenance of bipolar disorder, where it illustrated a lower risk of recurrence than placebo (Geddes 2009; Miura 2014; Oya 2019). It has also been reported to be equally effective as lithium, which is the standard treatment for bipolar disorder (Suppes 2008). In addition, lamotrigine demonstrated a better safety profile compared to lithium in postpartum teratogenicity (Graham 2018), although available evidence from a population‐based cohort study found that it was equivalent to lithium in the prevention of (hypo) manic or depressive episodes (Wesseloo 2017). It is worth highlighting that lamotrigine has been proposed as a treatment option for bipolar disorder during pregnancy among mothers who are at risk of depression. For example, Kong 2018 indicated that lamotrigine could be a safe mood stabilizer for use during pregnancy based on available clinical evidence; one systematic review found that lamotrigine was associated with a better safety profile in terms of congenital malformations (Gimenez 2019). However, since the available supporting evidence was derived from small‐scale studies, the precise benefits and harms of lamotrigine during pregnancy remain unclear.

How the intervention might work

Lamotrigine is an antiepileptic drug belonging to the phenyltriazine class used in the treatment of epilepsy and bipolar disorder. Lamotrigine works by inhibiting voltage‐sensitive sodium channels, stabilizing presynaptic neuronal membranes and inhibiting glutamate release (Verrotti 2018). The proposed mechanisms of action to explain the treatment of lamotrigine for bipolar disorder include inhibiting voltage‐sensitive sodium channels, glutamate release and calcium channel blockade (Andreazza 2014). To reduce the risk of life‐threatening skin rashes, lamotrigine needs to be titrated slowly. Thus, lamotrigine is more effective as maintenance therapy than in the acute treatment of bipolar disorder (Bobo 2017; Calabrese 2008). Although the effects of lamotrigine on pregnancy have been reported in a previous systematic review, there was no association with birth defects or related disorders (Pariente 2017). Lamotrigine has been shown to demonstrate more predictable pharmacokinetics than other antiepileptic drugs such as carbamazepine and valproic acid or valproate, which have a pronounced interindividual variability in their pharmacokinetics and a narrow therapeutic range (Johannessen 2006). As with other antiepileptic drugs, there are demonstrable effects of metabolic enzymes but oral bioavailability is almost 100%, with negligible influence from diets (Garnett 1997). Consequently, treatment of lamotrigine is associated with less burden in blood sampling/therapeutic monitoring inflicted on people with bipolar disorder.

Why it is important to do this review

Reviews exploring the effectiveness of lamotrigine are available (Bowden 2012; Yatham 2018). However, these existing reviews considered non‐maintenance therapies as part of their scope, and the numbers of included studies and study participants were small. Consequently, we plan to conduct this Cochrane systematic review to capture the latest available randomized evidence in order to provide a comprehensive update on the effectiveness of lamotrigine for maintenance treatment of bipolar disorder. Although lithium is used as the first‐line drug for the treatment of bipolar disorder, results from randomized studies on the comparative efficacy of lamotrigine versus lithium are inconsistent and thus we hope to review and synthesize evidence using rigorous and systematic methods. We will examine the effectiveness of lamotrigine against placebo as well as combination therapy and existing medications.

Objectives

To determine efficacy and safety of lamotrigine for the maintenance treatment of manic, depressive, and mixed episodes of bipolar disorder.

Methods

Criteria for considering studies for this review

Types of studies

We will include individually randomized and cluster‐randomized controlled trials. We will also include studies employing a cross‐over design using only data from the first active treatment (i.e. first phase before crossing over). We will include studies published as full texts, studies published only as a summary and unpublished data.

Types of participants

We will include people with bipolar I or II disorder in remission, with a diagnosis based on the International Classification of Diseases 11th Revision (ICD‐11) coding system (WHO 2019b), or the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM‐5) tool (or previous versions of these diagnostic manuals) (American Psychiatric Association 2013). Study participants will be aged 18 years or older of either gender with concurrent primary diagnosis of Axis I or Axis II disorder. We will include participants with any comorbidities except for those with dementia and personality disorder or cyclothymia, which is defined as a disorder not meeting the requirements to be classified as a major episode of hypomanic and depressive state.

Types of interventions

We will include trials comparing lamotrigine with usual care, placebo or no treatment; the daily dosage of lamotrigine maintenance treatment will be 100 mg to 500 mg with a treatment duration of more than 12 weeks. We will investigate the following comparisons:

• lamotrigine versus no treatment;

• lamotrigine versus placebo;

• lamotrigine versus lithium;

• lamotrigine versus valproic acid or valproate (or both);

• lamotrigine versus olanzapine;

• lamotrigine versus quetiapine;

• lamotrigine plus lithium versus lithium;

• lamotrigine plus lithium versus lamotrigine;

• lamotrigine plus valproic acid or valproate (or both) versus valproic acid or valproate (or both);

• lamotrigine plus valproic acid or valproate (or both) versus lamotrigine;

• lamotrigine plus olanzapine versus olanzapine;

• lamotrigine plus olanzapine versus lamotrigine;

• lamotrigine plus quetiapine versus quetiapine;

• lamotrigine plus quetiapine versus lamotrigine.

Types of outcome measures

Primary outcomes

• Recurrence of any episode for one year, defined as follows:

  • hospitalization for any mood episodes;

  • Young Mania Rating Scale (YMRS) total score 15 or greater for manic episode (Young 1978);

  • Montgomery‐Asberg Depression Rating Scale (MADRS) total score 15 or greater for depressive episode (Montgomery 1979); Hamilton Depression Rating Scale (HDRS) total score 14 or greater for depressive episode (Hamilton 1960);

  • clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication or benzodiazepine; or

  • active suicidal behaviour.

• Withdrawal from treatment due to any reason:

  • short‐term, up to 12 weeks after initiating the intervention;

  • long‐term, six and 12 months after initiating the intervention.

• Any reported adverse effects:

  • short‐term, up to 12 weeks after initiating the intervention;

  • long‐term, six and 12 months after initiating the intervention.

Secondary outcomes

• Recurrence of manic episode for one year.

• Recurrence of depressive episode.

• Quality of life as measured by the mental component summary of the 36‐Item Short Form Health Survey (SF‐36) (Ware 1993).

• Total severity score calculated from adding depression and manic symptom scores, such as the HDRS and the YMRS (Hamilton 1960; Young 1978).

Timing of outcome assessment

We anticipate that authors of studies will report response rates at various time points during and postintervention. Therefore, we will subdivide the timing of outcome assessment as follows:

• short‐term effects, measured up to 12 weeks after initiating of the intervention;

• long‐term effects, six or 12 months (or both) after initiating of the intervention.

Hierarchy of outcome measures

If several measures are available for each outcome, we will use results from the HDRS. If HDRS results are not available, we will use results from MADRS for depressive episode of the primary outcome. However, if outcomes are measured by other rating scales, we will include and extract these results with explanations on the components of the scale used by the respective included studies.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (description in Appendix 1) as well as the following electronic databases from inception:

• Cochrane Central Register of Controlled Trials (CENTRAL), (current issue) in the Cochrane Library;

• Ovid MEDLINE (1946 onwards);

• Ovid Embase (1974 onwards);

• Ovid PsycINFO (all available years).

We will adapt the preliminary search strategy for MEDLINE as illustrated in Appendix 2 for use in the other databases. We will search ClinicalTrials.gov (clinicaltrials.gov/), and the World Health Organization International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/), to identify unpublished or ongoing studies. We impose no restrictions on language, publication year or publication status.

Searching other resources

We will screen reference lists of relevant narrative reviews and included studies for further relevant information.

For information on unpublished data or ongoing studies, we will contact the study investigators or content experts in the field (or both) in an attempt to identify additional trial data.

Data collection and analysis

Selection of studies

Two review authors (YH and KK) will independently screen titles and abstracts from the systematic search, and will exclude clearly irrelevant records. For any disagreements, we will consult other review authors (TF or SS, or both). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, not each reference, is the unit of interest in the review.

We will retrieve full‐text versions of all 'include' and 'unclear' records for further assessment against our predefined eligibility criteria. We will attempt to obtain translations of articles that are published in languages other than English or Japanese. For conference abstracts, we will attempt to retrieve relevant subsequent full‐text publication or contact the study authors for clarification or further information. Two review authors (YH and KK) will independently screen the full texts against the inclusion/exclusion criteria. We will resolve disagreements by discussion or by consulting other review authors (TF or SS, or both). We will illustrate our study selection process using a PRISMA flow diagram (Moher 2009).

Data extraction and management

Two review authors (YH and KK) will independently extract the following information from included studies using a prestandardized form:

• methods: study design, total duration of study, methods of randomization, methods of allocation concealment, withdrawals;

• participants: number, mean age, age range, gender, inclusion and exclusion criteria, diagnosis (bipolar disorder I type or type II), baseline comparability between two groups, severity of condition, mean scores on HDRS, or MADRS, or any other episode scale at baseline and end of studies, time from onset and losses to follow‐up;

• interventions: intervention, comparison, concomitant medications and excluded medications;

• outcomes: primary and secondary;

• others: setting, publication year, sources of funding, intention‐to‐treat (ITT) analysis.

We will resolve any disagreements regarding the extracted study information by consulting other review authors (TF or SS, or both).

Assessment of risk of bias in included studies

Two review authors (YH and KK) will independently assess risk of bias in included studies using Cochrane's tool for assessing risk of bias as indicated in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements by discussion or by consulting other review authors (TF or SS, or both).

We will assess the risk of bias in included studies according to the following seven domains:

• random sequence generation;

• allocation concealment;

• blinding of participants and personnel;

• blinding of outcome assessment;

• incomplete outcome data;

• selective outcome reporting;

• other bias.

We will judge each potential source of bias as 'high risk', 'low risk' or 'unclear risk', and provide a supporting quotation from the study report together with a justification for our judgements in the 'Risk of bias' table. We will summarize the 'Risk of bias' judgements across different studies for each domain.

Measures of treatment effect

For continuous data such as quality of life, if the included studies reported using the same measurement scale, we will synthesize mean differences (MDs) with 95% confidence intervals (CIs). Should studies use different measurement tools, we will calculate standardized mean differences (SMDs). For dichotomous data such as number of reported adverse effects, we will synthesize risk ratios (RRs) with 95% CIs. For studies that report only hazard ratios (HRs), we will combine the data with those reported as RRs.

Unit of analysis issues

Cross‐over studies

One concern of cross‐over trials is the carry‐over effect, where the anticipated and unprecedented pharmacological, physiological and psychological effects of the study treatment intervention in the first phase may affect the results of the second phase of the study. As a result, in the second phase, participants can differ systematically from their initial state, even after a washout period. Therefore, we will consider only results from the first phase, that is, prior to the cross‐over.

Cluster‐randomized trials

For cluster‐randomized trials, we will make an adjustment to the sample size for each intervention based on the method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using an estimate of the intraclass correlation coefficient (ICC) derived from the study (where available) or from a similar study or from a study of a similar population. We will conduct a sensitivity analysis to explore the effects of variation in ICCs and the overall robustness of our findings (Sensitivity analysis).

Studies with multiple treatment groups

Where a relevant study involves more than two treatments groups, we will include data from the additional arms for comparisons. If the data are binary, we will combine them in a 2 × 2 table. If data are continuous, we will combine data following the formula provided in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011).

Dealing with missing data

We will record missing data for each included study and we will contact the study investigators to obtain missing information. If possible, we will perform all meta‐analyses using an ITT approach, that is, we will analyze all participants and their outcomes within the groups to which they were originally allocated, regardless of whether they received the intervention. When ITT data are not available/reported in the included studies, we will adopt the available‐case analysis.

Assessment of heterogeneity

We will evaluate heterogeneity by visually inspecting the calculated effect estimates and CIs in the forest plots. We will also use the Chi² test (statistical significance at P < 0.1) and the I² statistic to investigate and quantify statistical heterogeneity in each meta‐analysis. We will interpret the I² statistic as follows (Higgins 2011):

• 0% to 40% might not be important;

• 30% to 60% may represent moderate heterogeneity;

• 50% to 90% may represent substantial heterogeneity;

• 75% to 100% represents considerable heterogeneity.

Assessment of reporting biases

Reporting biases arise when dissemination of research findings is influenced by the nature and direction of the results (Higgins 2011). Should sufficient evidence be available (10 or more included studies), we will produce a funnel plot to investigate publication bias through visual inspection of asymmetry. We will also perform a statistical test for funnel plot asymmetry as proposed by Egger and Rücker (Egger 1997; Rücker 2008).

Data synthesis

One review author (KK) will enter data into Review Manager 5 (Review Manager 2014), and a second review author (YH) will check the entries. When it is reasonable to assume that studies are homogeneous, that is, examining the same intervention in similar populations using the same methods, we will use a fixed‐effect model for meta‐analysis. If there is clinical heterogeneity (due to variations in participants, interventions or outcomes), we will use a random‐effects meta‐analysis to produce an overall summary if it is reasonable to assume that an average treatment effect across the included studies is clinically meaningful. If not, we will not perform a meta‐analysis and instead will present a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses for our primary outcomes:

• with or without mental disorder comorbidities;

• duration of treatment (up to six months and longer than six months);

• setting (community versus hospital);

• for each pharmacological modality such as mood stabilizer, antipsychotic and antidepressant.

To explain anticipated heterogeneity among study results, we define three congenital hypotheses on which our subgroup analysis approach is based.

We will compare subgroups using the formal test for subgroup differences in Review Manager 5 (Review Manager 2014).

Sensitivity analysis

In addition to the aforementioned sensitivity analysis to investigate the effects of ICCs (Unit of analysis issues), we will conduct sensitivity analyses under the following conditions to explore if risk of bias domains will affect the overall robustness of our findings:

• excluding studies with inadequate allocation concealment and random sequence generation;

• excluding studies in which outcome evaluation was not blinded;

• excluding studies in which loss to follow‐up was not reported or was greater than 10%;

• excluding studies funded by the pharmaceutical company marketing lamotrigine.

Summary of findings and assessment of the certainty of the evidence

We will prepare a 'Summary of findings' table using the GRADE system with GRADEpro GDT software for each of the main comparisons, considering the two most clinically important primary outcomes (Guyatt 2011). Two review authors (YH and KK) will independently grade the body of evidence using adapted decision rules. We will explore the following domains: risk of bias, inconsistency, indirectness, imprecision and publication bias. We will grade the overall strength of evidence for each outcome as 'high', 'moderate', 'low' or 'very low', and we will resolve any disagreement through discussion or referral to an arbitrator (TF or NW).

We will include the following outcomes in the 'Summary of findings' tables.

• recurrence of any episode for one year, defined as follows:

  • hospitalization for any mood episodes;

  • YMRS total score 15 or greater for manic episode;

  • MADRS total score 15 or greater for depressive episode; and HDRS total score 14 or greater for depressive episode;

  • clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication or benzodiazepine; or

  • active suicidal behaviour.

• Withdrawal from treatment due to any reason

  • short‐term, up to 12 weeks after initiating the intervention;

  • long‐term, six and 12 months after initiating the intervention.

Appendices

Appendix 1. Description of the CCMDCTR

Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR)

The Cochrane Common Mental Disorders Group (CCMD) retains two clinical trials registers at its editorial base (current to June 2016); a References Register and a studies‐based register. The CCMDCTR‐References Register contains over 40,000 reports of randomised controlled trials (RCTs) in disorders of anxiety, bipolar, depression, eating and psychological trauma, together with self‐harm. Approximately half of these references have been tagged to individual, coded trials. The coded trials are held in the CCMDCTR‐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, using a controlled vocabulary. (Please contact the CCMD Information Specialists for further details). Reports of trials for inclusion in the Group's registers were 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 were also sourced from international trial registers, pharmaceutical companies, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses.

Details of CCMD's generic search strategies (used to identify RCTs) can be found on the Group's website, with an example of the core MEDLINE search displayed below.

Core search strategy used to inform the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR): OVID MEDLINE
 A weekly search alert based on condition + RCT filter only
 1. [MeSH Headings]:
 eating disorders/ or anorexia nervosa/ or binge‐eating disorder/ or bulimia nervosa/ or female athlete triad syndrome/ or pica/ or hyperphagia/ or bulimia/ or self‐injurious behavior/ or self mutilation/ or suicide/ or suicidal ideation/ or suicide, attempted/ or mood disorders/ or affective disorders, psychotic/ or bipolar disorder/ or cyclothymic disorder/ or depressive disorder/ or depression, postpartum/ or depressive disorder, major/ or depressive disorder, treatment‐resistant/ or dysthymic disorder/ or seasonal affective disorder/ or neurotic disorders/ or depression/ or adjustment disorders/ or exp antidepressive agents/ or anxiety disorders/ or agoraphobia/ or neurocirculatory asthenia/ or obsessive‐compulsive disorder/ or obsessive hoarding/ or panic disorder/ or phobic disorders/ or stress disorders, traumatic/ or combat disorders/ or stress disorders, post‐traumatic/ or stress disorders, traumatic, acute/ or anxiety/ or anxiety, castration/ or koro/ or anxiety, separation/ or panic/ or exp anti‐anxiety agents/ or somatoform disorders/ or body dysmorphic disorders/ or conversion disorder/ or hypochondriasis/ or neurasthenia/ or hysteria/ or munchausen syndrome by proxy/ or munchausen syndrome/ or fatigue syndrome, chronic/ or obsessive behavior/ or compulsive behavior/ or behavior, addictive/ or impulse control disorders/ or firesetting behavior/ or gambling/ or trichotillomania/ or stress, psychological/ or burnout, professional/ or sexual dysfunctions, psychological/ or vaginismus/ or Anhedonia/ or Affective Symptoms/ or *Mental Disorders/

2. [Title/ Author Keywords]:
 (eating disorder* or anorexia nervosa or bulimi* or binge eat* or (self adj (injur* or mutilat*)) or suicide* or suicidal or parasuicid* or mood disorder* or affective disorder* or bipolar i or bipolar ii or (bipolar and (affective or disorder*)) or mania or manic or cyclothymic* or depression or depressive or dysthymi* or neurotic or neurosis or adjustment disorder* or antidepress* or anxiety disorder* or agoraphobia or obsess* or compulsi* or panic or phobi* or ptsd or posttrauma* or post trauma* or combat or somatoform or somati#ation or medical* unexplained or body dysmorphi* or conversion disorder or hypochondria* or neurastheni* or hysteria or munchausen or chronic fatigue* or gambling or trichotillomania or vaginismus or anhedoni* or affective symptoms or mental disorder* or mental health).ti,kf.

3. [RCT filter]:
 (controlled clinical trial.pt. or randomized controlled trial.pt. or (randomi#ed or randomi#ation).ab,ti. or randomly.ab. or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or distribut* or expose* or fashion or number* or place* or recruit* or subsitut* or treat*)).ab. or placebo*.ab,ti. or drug therapy.fs. or trial.ab,ti. or groups.ab. or (control* adj3 (trial* or study or studies)).ab,ti. or ((singl* or doubl* or tripl* or trebl*) adj3 (blind* or mask* or dummy*)).mp. or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or randomized controlled trial/ or pragmatic clinical trial/ or (quasi adj (experimental or random*)).ti,ab. or ((waitlist* or wait* list* or treatment as usual or TAU) adj3 (control or group)).ab.)

4. (1 and 2 and 3)

Records were screened for reports of RCTs within the scope of the Cochrane Common Mental Disorders Group. Secondary reports of RCTs were tagged to the appropriate study record. Similar weekly search alerts were also conducted on OVID Embase and PsycINFO, using relevant subject headings (controlled vocabularies) and search syntax, appropriate to each resource.

Appendix 2. MEDLINE search

Ovid MEDLINE will be searched for this review, using the following search strategy to identify randomised controlled trials comparing lamotrigine with usual care, placebo or no treatment.

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily <1946 onwards>
 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
 1 lamotrigine/
 2 lamotrigin*.mp.
 3 (1 or 2)
 4 "bipolar and related disorders"/ or bipolar disorder/
 5 (mania or manic or hypomani*).mp.
 6 affective psychosis.mp.
 7 (rapid cycling or schizoaffective).mp.
 8 (psychos* or psychotic or anti‐psycho* or antipsycho*).ti,kf.
 9 or/4‐8
 10 (3 and 9)
 11 controlled clinical trial.pt.
 12 randomized controlled trial.pt.
 13 (randomi#ed or randomi#ation or randomi#ing).ti,ab,kf.
 14 (RCT or "at random" or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or recruit* or split or subsitut* or treat*))).ti,ab,kf.
 15 placebo*.ab,ti,kf.
 16 trial.ab,ti,kf.
 17 groups.ab.
 18 (control* and (trial or study or group*) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,kf,hw.
 19 ((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,kf.
 20 double‐blind method/ or random allocation/ or single‐blind method/)
 21 or/11‐20
 22 exp animals/ not humans.sh.
 23 (21 not 22)
 24 (10 and 23)
 
 ***************************

Contributions of authors

Conceiving the review: YH, KK.

Co‐ordinating the review: YH, KK, TF, SS.

Undertaking manual searches: YH, KK.

Organizing retrieval of papers: YH, KK.

Screening retrieved papers against inclusion criteria: YH, KK, TF, SS.

Appraising quality of papers: YH, KK, NW, TF.

Extracting data from papers: YH, KK, TF, SS.

Providing additional data about papers: YH, KK.

Obtaining and screening data on unpublished studies: YH, KK.

Data management for the review: YH, KK.

Entering data into Review Manager 5: YH, KK.

Review Manager 5 statistical data: YH, KK.

Other statistical analysis not using Review Manager 5: YH, KK.

Double entry of data: data entered by person one, YH; data entered by person two, KK.

Interpretation of data: YH, KK, NW, TF, SS.

Statistical inferences: YH, KK, NW, TF, SS.

Writing the review: YH, KK.

Securing funding for the review: YH, KK.

Performing previous work that was the foundation of the present study: YH, KK, TF, SS.

Guarantor for the review: YH.

Person responsible for reading and checking review before submission: YH.

Sources of support

Internal sources

• Kobe Gakuin University, Japan.

  Research funding

External sources

• None, Other.

Declarations of interest

YH: none.

KK: none.

NW: none.

TF: none.

SS: none.

New