bmj open · antipsychotic long acting injections (lais) have been suggested to improve adherence...

For peer review only

Efficacy and safety of second generation antipsychotic long acting injections (SGA LAIs) in maintenance treatment of

bipolar disorder: protocol for a systematic review and meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2015-010237

Article Type: Protocol

Date Submitted by the Author: 12-Oct-2015

Complete List of Authors: PRAJAPATI, ASTA; Norfolk and Suffolk NHS Foundation Trust, Pharmacy Wilson, Jonathan; Norfolk and Suffolk NHS Foundation Trust Maidment, Ian; Aston University, Pharmacy

<b>Primary Subject Heading</b>:

Mental health

Secondary Subject Heading: Pharmacology and therapeutics

Keywords: Bipolar disorder, Second generation antipsychotics, Atypical antipsychotics, Antipsychotic long acting injections, Antipsychotic depots

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1. Title: “Efficacy and safety of Second Generation Antipsychotic Long Acting

Injections (SGA LAIs) in maintenance treatment of bipolar disorder: study

protocol for a systematic review and meta-analysis”

2. Author: Mr Asta Ratna Prajapati, Clinical Pharmacy Manager, Pharmacy Department, Hellesdon Hospital, Norfolk and Suffolk NHS Foundation Trust, Drayton High Road, Norwich, NR6 5BE, UK. E.mail: [email protected], Tel: 01603 421 606, Fax: 01603 421

3. Co-authors: Dr Jonathan Wilson, Deputy Medical Director, Research,

Norfolk and Suffolk NHS Foundation Trust, Norfolk, UK.

Dr Ian Maidment, Senior Lecturer, Pharmacy, Aston University, Birmingham, UK.

4. Keywords: Second Generation Antipsychotics, Long Acting Injections, Atypical antipsychotics, Bipolar Disorder, Antipsychotic depots

5. Word count: 2683 (excluding references, title page and flowchart).

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Efficacy and safety of second generation antipsychotic long acting injections

(SGA LAIs) in maintenance treatment of bipolar disorder: protocol for a

systematic review and meta-analysis

Abstract

Introduction: Bipolar disorder requires long term treatment but non-adherence is a

common problem. Antipsychotic long acting injections (LAIs) have been suggested

to improve adherence but none are licensed in the UK for bipolar. However, the use

of Second Generation Antipsychotics (SGA) LAIs in bipolar is not uncommon albeit

there is a lack of systematic review in this area. This study aims to systematically

review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar

disorder. Methods and analysis: The protocol is based on Preferred Reporting

Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only

randomized controlled trials comparing SGA LAIs in bipolar. Pubmed, Embase,

CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, www.clinicaltrials.gov

will be searched, with no language restriction, from 2000 to Jan 2016 as first SGA

LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be

contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or

reduction in hospitalization and primary safety outcomes are drop-out rates, all-

cause discontinuation and discontinuation due to adverse events. Qualitative

reporting of evidence will be based on 21 items listed on standards for reporting

qualitative research (SRQR) focusing on study quality (assessed using the Jadad

score, allocation concealment and data analysis), risk of bias and effect size.

Publication bias will be assessed using funnel plots. If sufficient data are available

meta-analysis will be performed with primary effect size as relative risk presented

with 95% confidence interval. Sensitivity analysis, conditional on number of studies

and sample size, will be carried out on manic vs. depressive symptoms and

monotherapy vs. adjunctive therapy.

Ethics and dissemination: Ethical approval is not required as primary data will not

be collected. The results will be disseminated through a peer-reviewed publication,

conference presentation and the press.

Study registration number: PROSPERO CRD42015023948

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Strengths and Limitations of this study:

• Systematic review and meta-analysis of randomised controlled trials provide

the highest level of evidence to key stakeholders.

• This systematic review will search comprehensive list of databases using well

defined search strategy, will contact manufacturers for any unpublished

and/or ongoing trials.

• This study will clarify the position of second generation antipsychotics (SGAs)

long acting injections (LAIs) in maintenance treatment of bipolar disorder.

• Qualitative evidence summary and meta-analysis will address some highly

relevant clinical questions in bipolar disorder. Subgroup analyses will further

enhance the applicability of the results from this study.

• This review is focused on as SGA LAIs since first generation antipsychotics

are not considered preferred choice in maintenance treatment of bipolar

disorder due to risk of induction of depression.

• Lack of data and significant heterogeneity may prevent meta-analysis.

Background

The lifetime prevalence of bipolar I disorder is estimated at 1% of the adult

population, and bipolar II disorder affects approximately 0.4% of adults (1). Bipolar

disorder featuring mood and activity level disturbance is a recurrent disorder; it

usually requires long term maintenance therapy to prevent future mood episodes -

the primary goal of treatment (2). Lithium remains the gold standard prophylactic

treatment for bipolar disorder (1). However lithium may not be suitable for all patients

due to a lack of response or adverse events, or patients may not accept lithium due

to various reasons including monitoring requirement and/or side effects (3). Thus,

many patients require alternative prophylactic treatment for bipolar disorder. Many

guidelines including British Association of Psychopharmacology (4), The World

Federation of Societies of Biological Psychiatry (WFSBP) (5) and National Institute

for Health and Care Excellence (NICE) (1) from the UK recommend some Second

Generation Antipsychotic (SGA, also known as atypical antipsychotics) as a long

term treatment option for bipolar disorder; and many oral SGAs are licensed in the

UK for this indication (6).

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Non-adherence to the prescribed treatment is a major problem and common in

bipolar disorder with estimated frequency of non-adherence between 10% and 60%

(median 40%) (7). Non-adherence to treatment in bipolar disorder increases the risk

of relapse and suicide (8); and increased risk of rehospitalisation (7). Long Acting

Injections (LAIs, also known as depots) have some clear advantages due to

assurance that medication will be administered and the opportunity for healthcare

professionals to step in immediately if patients stop treatment (9). Evidence from

studies in people with schizophrenia suggests antipsychotics LAIs reduce relapses,

reduce medication discontinuation rates and improve outcomes compared to oral

antipsychotics although Cochrane review of various depots did not find any

convincing difference (9). However, these reviews also included in-patient studies,

short term trials of just a few weeks duration (9) and mostly included only First

Generation Antipsychotic (FGA, also known as typical antipsychotics) LAIs. LAIs

formulations have other Pharmacological advantages: more predictable

bioavailability since LAIs medications bypass gastrointestinal absorption and the

effect of first-pass hepatic metabolism, more stable plasma levels compared to oral

antipsychotics, sustained medication plasma levels at the therapeutic range (7).

The use of SGA LAIs in the maintenance treatment of bipolar disorder has ignited

interest for improving adherence and reducing the risk of relapse (7). Over the last 5

years two new SGA LAIs, aripiprazole and paliperidone, have been introduced in the

UK. However, none of the SGA LAIs are currently licensed for bipolar disorder in the

UK (6) albeit clinical experience suggests their uses for this indication are not

infrequent. Recent (2011) mixed-treatment meta-analysis suggests that

antipsychotics are more effective than mood stabilisers in the treatment of mania

(10). Some studies have found that risperidone LAI is effective for maintenance

treatment in bipolar disorder (7). Risperidone LAI is also approved by US FDA for

monotherapy or as adjunctive therapy to lithium or valproate for the maintenance

treatment of Bipolar I Disorder (11).

Despite these potential advantages of antipsychotic LAIs in the treatment of bipolar

disorder there is a lack of any properly conducted systematic review. During a

scoping search, two literature reviews conducted within last 5 years were identified

(7, 8). Literature reviews do provide a useful overview of the subject; however they

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generally lack the rigour of systematic reviews. Systematic reviews of well-designed

randomized controlled trials (RCTs) are considered gold-standard and top of the

evidence hierarchy in healthcare research (13-15). A systematic review with a

focused clinical question with clear specifications searches all relevant databases

with pre-defined systematic search strategy and using pre-specified eligibility criteria

for studies to be included. A systematic review also provides the assessment of the

quality of the studies included in the review aiming to avoid bias and therefore

support evidence based practice. With pre-defined protocol good systematic reviews

provide robust evidence to support or change clinical practice.

Gigante et al. (7) reviewed evidence of FGAs and SGA LAIs in bipolar disorder

searching pubmed from 1950 to 2011 and published in English. This review included

all types of studies from randomised controlled trials (RCTs) to retrospective chart

reviews in their evidence synthesis. In terms of SGA LAIs only literatures pertaining

to risperidone LAI were found. The level of evidence is limited due to small number

(n=2) of large RCTs. No RCTs were found involving other SGA LAIs except

risperidone. The authors concluded that FGA LAI should not be a first choice due to

risk of induction of depression but suggested risperidone LAI is effective in bipolar.

This is consistent with previous literature review by Bond et al. 2007 (16).

Recently (2014) Samalin et al. (8) carried out another review of SGA LAIs in bipolar

disorder and concluded that risperidone LAI may be considered for maintenance

treatment of bipolar disorder but more evidence is required. This review included

RCTs, case series and did not include any specific inclusion / exclusion criteria, did

not perform quality assessment, focused the search on pubmed and embase and no

information gathered from manufacturers. The authors carried out last search in April

2013 which gives us around two and half years of potential extra literature, a good

time frame to review evidence in this moving field. In addition, Samalin et al. found

studies only on risperidone LAI and this systematic review is expected to find studies

related to other SGA as scoping exercise found some ongoing active studies of other

SGA LAI.

This systematic review will include only RCTs comparing SGA LAIs with placebo or

other antipsychotics or mood stabilizers or treatment as usual; search many other

relevant databases as listed in the methodology section; contact manufacturers for

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further trials (both ongoing and unpublished trials), quality assess all included

studies; and investigate risk of bias. The protocol is registered with PROSPERO-

www.crd.york.ac.uk/PROSPERO/ - international prospective register of systematic

reviews.

The result of this study will have an impact on clinical practice and prescribing

decision either to support or discourage use of SGA LAIs in maintenance treatment

of bipolar disorder. It is author’s intention to publish the result of this study in a peer

reviewed journal and to widely communicate with key clinical and academic

stakeholders both nationally and internationally. The result from the study will close

the evidence gap and thus inform healthcare professionals and patients of the

evidence or lack of it in using SGA LAIs in bipolar disorder.

Objective

To conduct systematic review of RCTs evaluating efficacy and safety of SGA LAIs in

maintenance treatment of bipolar disorder.

Methodology

The research protocol is based on PRISMA, Preferred Reporting Items for

Systematic reviews and Meta-Analyses (17). Specific PICOS; participants,

interventions, comparators, outcomes, and study design; detailed below will be used

for study selection criteria:

1) Inclusion criteria for selecting studies for this review:

Any studies not meeting following inclusion criteria will be excluded.

A. Participants: patients of any age or sex with bipolar disorder using any

validated diagnostic system, e.g. Diagnostic and Statistical Manual of

Mental Disorders (DSM-V: 296) or the International Classification of

Diseases (ICD 10: F31).

B. Interventions: SGA LAIs in bipolar disorder

C. Comparators: placebo, other antipsychotics, mood stabilizer or

treatment as usual

D. Outcome measures:

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I. Primary efficacy outcome - relapse rate or delayed time to

relapse or reduction in hospitalization

II. Primary safety outcome - drop-out rates or all-cause

discontinuation, discontinuation due to adverse events

III. Secondary outcomes may include changes in BDRS (Bipolar

Disorder Rating Scale) or YMRS (Young Mania Rating Scales),

discontinuation due to hospitalization, and non-adherence (study

defined), safety outcome of SGA LAIs e.g. EPSEs and

metabolic adverse effect – weight gain, hyperglycaemia,

dyslipidaemia, hyperprolactinaemia.

E. Study design: RCTs with or without double blinding with minimum

duration of 6 months. It is anticipated that most studies will be out-

patient as non-adherence in in-patients is unlikely due to staff

administration. Nonetheless this study will include both out-patients

and in-patients as some units are long stay in-patient units in secure

services or rehabilitation units and since sustained therapeutic plasma

level has been suggested as a pharmacological advantage of LAIs in

addition to improvement in adherence.

Data sources, search strategy and study selection

Missing any relevant and significant study may render the systematic review

less credible. The following detailed search strategy will be employed to

ensure all relevant studies are captured, independently analysed, verified and

quality assessed.

A comprehensive, electronic search strategy will be used to identify relevant

RCTs in humans where SGA LAIs are being assessed for efficacy and safety

in bipolar disorder. There will be no language restrictions. Studies published

between January 2000 and Jan 2016 will be searched since SGA LAIs came

to the market only after 2000. The searches will be re-run just before the final

analyses and any further eligible studies retrieved for inclusion.

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Following databases will be searched: Pubmed, Embase, CINAHL, Cochrane

Library (CENTRAL), PsychINFO, LiLACS, www.clinicaltrials.gov. Any relevant

studies mentioned in those identified studies will be searched manually, for

example scoping the references listed. Manufacturers of SGA LAIs will be

contacted for any ongoing or unpublished studies.

To capture all relevant studies the search strategy will consist of three

domains: disease (bipolar disorder), treatment (SGA) and formulation (LAIs).

Each domains will be searched using many terms (as listed below) with

Boolean search operator “OR”. The Boolean search operator “AND” will be

used to connect these three domains.

a) Disease domain: bipolar*, mood disorder*, mania*, manic-depression*,

hypomania*, AND

b) Treatment domain: antipsychotic*, neuroleptic*, psychotropic*,

atypical*, second generation antipsychotic*, SGA*, aripiprazole,

olanzapine, paliperidone, risperidone, ziprasidone AND

c) Formulation domain: depot*, long-acting injection*, LAI*, prolonged

release injection*, sustained release injection*

The process; of identifying, screening of studies and inclusion or exclusion of

those studies; is shown in the PRISMA flow diagram below:

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3. Data collection, analysis and quality assessment

A list of all identified studies from all the resources searched will be created.

Any other studies mentioned or referred to in these studies which seem

relevant to the review will be hand searched. Titles of all the studies retrieved

using the search strategy and those from additional sources will be screened

for their relevance to the review. Definite non-relevant studies will be excluded

“N” records identified through

database searching

“n” additional records identified through

other sources e.g. Manufacturers, hand

search

{(N+n)-X}= N1 records after duplicates (X) removed

(N1– X1) = N2 titles screened X1 records excluded, with

reasons

(N2-X2) = N3 abstracts assessed

N4 of studies included in

qualitative synthesis

X2 abstracts excluded, with

reasons

(N4-X4) = N5 of studies

included in meta-analysis

(N3-X3) = N4 of full-text articles

assessed

X3 full-text articles excluded,

with reasons

X4 studies not suitable for

meta-analysis

Iden

tifi

cati

on

S

cree

nin

g

Eli

gib

ilit

y

Incl

ud

ed

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while relevant, ambiguous or unclear studies will be included for screening

abstract.

All the articles will be screened for its title to check their relevance by lead

author (AP) and second reviewer (JW). Abstracts of the remaining studies,

after discarding definite irrelevant studies, will be screened by the lead author

(AP) and second reviewer (JW) to identify studies that potentially meet the

inclusion criteria outlined above. The second reviewer (JW) will review titles

and abstract independently and list studies to be included and those to

exclude. Any disagreement between two reviewers over the eligibility of

particular studies will be resolved through further discussion and / or with third

reviewer (IM) involvement.

A standardised, pre-piloted form will be used to extract data from the included

studies for assessment of study quality and evidence synthesis. Extracted

information will include: study design; study population and participant

demographics and baseline characteristics; details of the intervention and

control conditions; study methodology; recruitment and study completion

rates; outcomes and times of measurement; information for assessment of the

risk of bias. The lead reviewer (AP) will extract the data and any ambiguity/

questions will be discussed with 2nd (JW) and / or 3rd (IM) reviewer. Missing

data will be requested from study authors.

Study quality will be assessed using Cochrane collaboration's risk of bias tool

and publication bias by visual inspection of funnel plots (18).

Narrative qualitative evidence synthesis will be provided on aggregate level on

study outcome for their primary and secondary outcome. Qualitative reporting

of evidence will be based on 21 items listed on standards for reporting

qualitative research (SRQR) (19). Total number of patients in the study, study

quality, risk of bias and effect size will be detailed on qualitative evidence

summary.

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Meta-analysis

It is authors’ intention to undertake quantitative meta-analysis. If study data

and sample size are sufficient meta-analysis will be performed. Statistical

significance will be set at 0.05 with value <0.05 considered statistically

significant. The primary effect size will be relative risk presented with 95%

confidence interval. The analysis will be based on intention-to-treat where

data available. Study heterogeneity will be measured using I2-statistic

considering values of 50% or higher to reflect considerable heterogeneity

which will be investigated.

Sensitivity analysis

If sufficient number of studies and sample size are available, sensitivity

analysis will be carried out on manic vs. depressive symptoms and

monotherapy vs. adjunctive therapy or different antipsychotic.

Ethical approval: This systematic review does not require ethical approval, as data

used here are not individual or private and there will be no primary data collection.

Funding statement: This research received no specific grant from any funding

agency in the public, commercial or not-for-profit sectors.

Authors: Asta R Prajapati (AP), Clinical Pharmacy Manager, Pharmacy Department,

Dr Jonathan Wilson (JW), Deputy Medical Director, Research, both at

Norfolk and Suffolk NHS Foundation Trust; Dr Ian Maidment (IM), Senior

Lecturer, Pharmacy, Aston University.

Correspondence: [email protected]

Declarations of interest: AP- None. IM has received speaker honoraria from

Astellas Pharmaceuticals. JW - waiting confirmation (currently on leave).

Author’s contribution: AP and IM conceived the study. AP drafted the protocol and

registered with PROSPERO. IM helped design the protocol

and reviewed protocol. JW reviewed the protocol. All authors

have approved the publication of this protocol.

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Efficacy and safety of second generation antipsychotic long acting injections (SGA LAIs) in maintenance treatment of

bipolar disorder: protocol for a systematic review and meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2015-010237.R1

Article Type: Protocol

Date Submitted by the Author: 17-Nov-2015

Complete List of Authors: PRAJAPATI, ASTA; Norfolk and Suffolk NHS Foundation Trust, Pharmacy Wilson, Jonathan; Norfolk and Suffolk NHS Foundation Trust Maidment, Ian; Aston University, Pharmacy

<b>Primary Subject Heading</b>:

Mental health

Secondary Subject Heading: Pharmacology and therapeutics

Keywords: Bipolar disorder, Second generation antipsychotics, Antipsychotic, Depot preparation, Maintenance therapy


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1. Title: “Efficacy and safety of Second Generation Antipsychotic Long Acting

Injections (SGA LAIs) in maintenance treatment of bipolar disorder: study

protocol for a systematic review and meta-analysis”

2. Author: Mr Asta Ratna Prajapati, Clinical Pharmacy Manager, Pharmacy Department, Hellesdon Hospital, Norfolk and Suffolk NHS Foundation Trust, Drayton High Road, Norwich, NR6 5BE, UK. E.mail: [email protected], Tel: 01603 421 606, Fax: 01603 421

3. Co-authors: Dr Jonathan Wilson, Deputy Medical Director, Research,

Norfolk and Suffolk NHS Foundation Trust, Norfolk, UK.

Dr Ian Maidment, Senior Lecturer, Pharmacy, Aston University, Birmingham, UK.

4. Keywords: Antipsychotics, Depot Preparations, Bipolar Disorder, Second Generation Antipsychotics, Maintenance Treatment

5. Word count: 2809 (excluding references, title page and flowchart).

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Efficacy and safety of second generation antipsychotic long acting injections

(SGA LAIs) in maintenance treatment of bipolar disorder: protocol for a

systematic review and meta-analysis

Asta R Prajapati (AP), Clinical Pharmacy Manager, Pharmacy Department, Dr

Jonathan Wilson (JW), Deputy Medical Director, Research, both at Norfolk and

Suffolk NHS Foundation Trust, UK; Dr Ian Maidment (IM), Senior Lecturer,

Pharmacy, Aston University, UK.

Correspondence: Asta Prajapati, Pharmacy Department, Hellesdon Hospital,

Drayton High Road, Norwich NR6 5BE, UK. E-mail: [email protected] Tel:

01603421212

Keywords: Antipsychotics, Depot Preparations, Bipolar Disorder, Second Generation

Antipsychotics, Maintenance Treatment

Word count: 2709 (excluding references, title page and flowchart

Abstract

Introduction: Bipolar disorder requires long-term treatment but non-adherence is a

common problem. Antipsychotic Long Acting Injections (LAIs) have been suggested

to improve adherence but none are licensed in the UK for bipolar. However, the use

of Second Generation Antipsychotics (SGA) LAIs in bipolar is not uncommon albeit

there is a lack of systematic review in this area. This study aims to systematically

review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar

disorder. Methods and analysis: The protocol is based on Preferred Reporting

Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only

randomized controlled trials comparing SGA LAIs in bipolar. Pubmed, Embase,

CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, www.clinicaltrials.gov

will be searched, with no language restriction, from 2000 to Jan 2016 as first SGA

LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be

contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or

reduction in hospitalization and primary safety outcomes are drop-out rates, all-

cause discontinuation and discontinuation due to adverse events. Qualitative

reporting of evidence will be based on 21 items listed on standards for reporting

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qualitative research (SRQR) focusing on study quality (assessed using the Jadad

score, allocation concealment and data analysis), risk of bias and effect size.

Publication bias will be assessed using funnel plots. If sufficient data are available

meta-analysis will be performed with primary effect size as relative risk presented

with 95% confidence interval. Sensitivity analysis, conditional on number of studies

and sample size, will be carried out on manic vs. depressive symptoms and

monotherapy vs. adjunctive therapy.

Ethics and dissemination: Ethical approval is not required as primary data will not

be collected. The results will be disseminated through a peer-reviewed publication,

conference presentation and the press.

Study registration number: PROSPERO CRD42015023948

Strengths and Limitations of this study:

• Systematic review and meta-analysis of randomized controlled trials provide

the highest level of evidence to key stakeholders.

• This systematic review will search a comprehensive list of databases using

well-defined search strategy; will contact manufacturers for any unpublished

and/or ongoing trials.

• This study will clarify the position of second generation antipsychotics (SGAs)

long acting injections (LAIs) in maintenance treatment of bipolar disorder.

• Qualitative evidence summary and meta-analysis will address some highly

relevant clinical questions in bipolar disorder. Subgroup analyses will further

enhance the applicability of the results from this study.

• This review is focused on as SGA LAIs since first generation antipsychotics

are not considered preferred choice in maintenance treatment of bipolar

disorder due to risk of induction of depression.

• Lack of data and significant heterogeneity may prevent meta-analysis.

Background

The lifetime prevalence of bipolar I disorder is estimated at 1% of the adult

population, and bipolar II disorder affects approximately 0.4% of adults (1). Bipolar

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disorder, featuring mood and activity level disturbance, is a recurrent disorder; it

usually requires long-term maintenance therapy to prevent future mood episodes -

the primary goal of treatment (2). Lithium remains the gold standard prophylactic

treatment for bipolar disorder (1). However lithium may not be suitable for all patients

due to a lack of response or adverse events, or patients may not accept lithium due

to various reasons including monitoring requirement and/or side effects (3). Thus,

many patients require alternative prophylactic treatment for bipolar disorder. Many

guidelines including British Association of Psychopharmacology (4), The World

Federation of Societies of Biological Psychiatry (WFSBP) (5), Canadian Network for

Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar

Disorders (ISBD) (6), and National Institute for Health and Care Excellence (NICE)

(1) from the UK recommend some Second Generation Antipsychotic (SGA, also

known as atypical antipsychotics) as a long-term treatment option for bipolar

disorder; and many oral SGAs are licensed in the UK for this indication (7).

Non-adherence to the prescribed treatment is a major problem and common in

bipolar disorder. Estimated frequency of non-adherence in bipolar range between

10% and 60% (median 40%) (8). Non-adherence increases the risk of relapse and

suicide (9); and increased risk of rehospitalisation (8). Long Acting Injections (LAIs,

also known as depots) have some clear advantages due to assurance that

medication will be administered and the opportunity for healthcare professionals to

step in immediately if patients stop treatment (10). Evidence from studies in people

with schizophrenia suggests antipsychotics LAIs reduce relapses, reduce medication

discontinuation rates and improve outcomes compared to oral antipsychotics

although some Cochrane reviews of various depots did not find any convincing

difference (10). However, these Cochrane reviews also included in-patient studies,

short-term trials of just a few weeks duration (10) and mostly included only First

Generation Antipsychotic (FGA, also known as typical antipsychotics) LAIs. LAIs

formulations have other Pharmacological advantages: more predictable

bioavailability since LAIs medications bypass gastrointestinal absorption and the

effect of first-pass hepatic metabolism, more stable plasma levels compared to oral

antipsychotics, sustained plasma levels of medication at therapeutic range (8).

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The use of SGA LAIs in the maintenance treatment of bipolar disorder has ignited

interest for improving adherence and reducing the risk of relapse (8). Over the last 5

years two new SGA LAIs, aripiprazole and paliperidone, have been introduced in the

UK. None of the SGA LAIs are currently licensed for bipolar disorder in the UK (7)

albeit clinical experience suggests their uses for this indication are not infrequent.

Recent (2011) mixed-treatment meta-analysis suggests that antipsychotics are more

effective than mood stabilisers in the treatment of mania (11). Some studies have

found that risperidone LAI is effective for maintenance treatment in bipolar disorder

(7, 8) and CANMAT recommends risperidone LAI as one of the first line treatment

options in maintenance treatment of bipolar disorder (6). Risperidone LAI is

approved by US FDA for monotherapy or as an adjunctive therapy to lithium or

valproate for the maintenance treatment of Bipolar I Disorder (12).

Despite these potential advantages of antipsychotic LAIs in the treatment of bipolar

disorder there is a lack of any properly conducted systematic review. During a

scoping search two literature reviews (8, 9) conducted within last 5 years were

identified (). Literature reviews offer a useful overview of the subject; however they

generally lack the rigour of systematic reviews. Systematic reviews of well-designed

randomized controlled trials (RCTs) are considered gold-standard and top of the

evidence hierarchy in healthcare research (13-15). A systematic review with a

focused clinical question with clear specifications searches all relevant databases

with pre-defined systematic search strategy and using pre-specified eligibility criteria

for studies to be included. A systematic review also provides the assessment of the

quality of the studies included in the review aiming to avoid bias and therefore

support evidence based practice. With pre-defined protocol good systematic reviews

provide robust evidence to support or change clinical practice.

Gigante et al. (8) reviewed evidence of FGAs and SGA LAIs in bipolar disorder

searching pubmed from 1950 to 2011 and published in English. This review included

all types of studies from randomised controlled trials (RCTs) to retrospective chart

reviews in their evidence synthesis. In terms of SGA LAIs only literatures pertaining

to risperidone LAI were found. The level of evidence is limited due to small number

(n=2) of large RCTs. No RCTs were found involving other SGA LAIs except

risperidone. The authors concluded that FGA LAI should not be a first choice due to

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risk of induction of depression but suggested risperidone LAI is effective in bipolar.

This is consistent with earlier literature review by Bond et al. 2007 (16).

Recently (2014) Samalin et al. (9) carried out another review of SGA LAIs in bipolar

disorder and concluded that risperidone LAI may be considered for maintenance

treatment of bipolar disorder but more evidence is required. This review included

RCTs, case series and did not include any specific inclusion / exclusion criteria; did

not perform quality assessment; focused the search on pubmed and embase; and no

information sought from manufacturers. The authors carried out last search in April

2013 which gives us around two and half years of potential extra literature, a good

time frame to review evidence in this moving field. In addition, Samalin et al. found

studies only on risperidone LAI and this systematic review is expected to find studies

related to other SGA as scoping exercise found some ongoing active studies of other

SGA LAI.

Chou et al. (2015) (17) authored an article titled “A Systemic Review and Experts’

Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder”. This was

an expert consensus building study and good endeavour for consensus report on the

topic but lacking any details on review process and methodology, a critical and

essential aspect of any systematic reviews. In addition, Chou et al looked at both

FGAs and SGAs and found studies pertaining to risperidone LAI only in terms of

SGA LAIs.

This systematic review will:

• include only RCTs comparing SGA LAIs with placebo or other antipsychotics

or mood stabilizers or treatment as usual;

• search many other relevant databases as listed in the methodology section;

• contact manufacturers for further trials (both ongoing and unpublished trials);

• quality assess all included studies and

• investigate the risk of bias.

The protocol is registered with PROSPERO- www.crd.york.ac.uk/PROSPERO/ -

international prospective register of systematic reviews.

The result of this study will have an impact on clinical practice and prescribing

decision either to support or discourage use of SGA LAIs in maintenance treatment

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of bipolar disorder. It is author’s intention to publish the result of this study in a peer

reviewed journal and to widely communicate with key clinical and academic

stakeholders both nationally and internationally. The result from the study will close

the evidence gap and thus inform healthcare professionals and patients of the

evidence or lack of it in using SGA LAIs in bipolar disorder.

Objective

To conduct systematic review and meta-analysis of RCTs evaluating efficacy and

safety of SGA LAIs in maintenance treatment of bipolar disorder

Methodology

The research protocol is based on PRISMA, Preferred Reporting Items for

Systematic reviews and Meta-Analyses (18). Specific PICOS; Participants,

Interventions, Comparators, Outcomes, and Study design; detailed below will be

used for study selection criteria:

1) Inclusion criteria:

Any studies not meeting following inclusion criteria will be excluded.

A. Participants: patients of any age or sex with bipolar disorder using any

validated diagnostic system, e.g. Diagnostic and Statistical Manual of

Mental Disorders (DSM-V: 296) or the International Classification of

Diseases (ICD 10: F31).

B. Interventions: SGA LAIs in bipolar disorder

C. Comparators: placebo, other antipsychotics, mood stabilizer or

treatment as usual

D. Outcome measures:

I. Primary efficacy outcome - relapse rate or delayed time to

relapse or reduction in hospitalization

II. Primary safety outcome - drop-out rates or all-cause

discontinuation or discontinuation due to adverse events

III. Secondary outcomes may include changes in BDRS (Bipolar

Disorder Rating Scale) or YMRS (Young Mania Rating Scales),

discontinuation due to hospitalization, and non-adherence (study

defined), safety outcome of SGA LAIs e.g. EPSEs and

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metabolic adverse effect – weight gain, hyperglycaemia,

dyslipidaemia, hyperprolactinaemia.

E. Study design: RCTs with or without double blinding with minimum

duration of 6 months. It is anticipated that most studies will be out-

patient as non-adherence in in-patients is unlikely due to staff

administration. Nonetheless this study will include both out-patients

and in-patients as some units are long stay in-patient units in secure

services or rehabilitation units and since sustained therapeutic plasma

level has been suggested as a pharmacological advantage of LAIs in

addition to improvement in adherence.

Data sources, search strategy and study selection

Missing any relevant and significant study may render the systematic review

less credible. The following detailed search strategy will be employed to

ensure all relevant studies are captured, independently analysed, verified and

quality assessed.

A comprehensive, electronic search strategy will be used to identify relevant

RCTs in humans where SGA LAIs are being assessed for efficacy and safety

in bipolar disorder. There will be no language restrictions. Studies published

between January 2000 and Jan 2016 will be searched since SGA LAIs came

to the market only after 2000. The searches will be re-run just before the final

analyses and any further eligible studies retrieved for inclusion.

Following databases will be searched: Pubmed, Embase, CINAHL, Cochrane

Library (CENTRAL), PsychINFO, LiLACS, www.clinicaltrials.gov. Any relevant

studies mentioned in those identified studies will be searched manually, for

example scoping the references listed. Manufacturers of SGA LAIs will be

contacted for any ongoing or unpublished studies.

To capture all relevant studies the search strategy will consist of three

domains: disease (bipolar disorder), treatment (SGA) and formulation (LAIs).

Each domains will be searched using many terms (as listed below) with

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Boolean search operator “OR”. The Boolean search operator “AND” will be

used to connect these three domains.

a) Disease domain: bipolar*, mood disorder*, mania*, manic-depression*,

hypomania*, AND

b) Treatment domain: antipsychotic*, neuroleptic*, psychotropic*,

atypical*, second generation antipsychotic*, SGA*, aripiprazole,

olanzapine, paliperidone, risperidone, ziprasidone AND

c) Formulation domain: depot*, long-acting injection*, LAI*, prolonged

release injection*, sustained release injection*

The process; of identifying, screening of studies and inclusion or exclusion of

those studies; is shown in the PRISMA flow diagram below:

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3. Data collection, analysis and quality assessment

A list will be created for all identified studies from all the resources searched.

Any other studies mentioned or referred to in these studies which seem

relevant to the review will be hand searched. Titles of all the studies retrieved

using the search strategy and those from additional sources will be screened

for their relevance to the review. Definite non-relevant studies will be excluded

“N” records identified through

database searching

“n” additional records identified through

other sources e.g. Manufacturers, hand

search

{(N+n)-X}= N1 records after duplicates (X) removed

(N1– X1) = N2 titles screened X1 records excluded, with

reasons

(N2-X2) = N3 abstracts assessed

N4 of studies included in

qualitative synthesis

X2 abstracts excluded, with

reasons

(N4-X4) = N5 of studies

included in meta-analysis

(N3-X3) = N4 of full-text articles

assessed

X3 full-text articles excluded,

with reasons

X4 studies not suitable for

meta-analysis

Identification

Screening

Eligibility

Included

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while relevant, ambiguous or unclear studies will be included for screening

abstract.

All the articles will be screened for its title to check their relevance by lead

author (AP) and second reviewer (JW). Abstracts of the remaining studies,

after discarding definite irrelevant studies, will be screened by the lead author

(AP) and second reviewer (JW) to identify studies that potentially meet the

inclusion criteria outlined above. The second reviewer (JW) will review titles

and abstract independently and list studies to be included and those to

exclude. Any disagreement between two reviewers over the eligibility of

particular studies will be resolved through further discussion and / or with third

reviewer (IM) involvement.

A standardised, pre-piloted form will be used to extract data from the included

studies for assessment of study quality and evidence synthesis. Extracted

information will include: study design; study population and participant

demographics and baseline characteristics; details of the intervention and

control conditions; study methodology; recruitment and study completion

rates; outcomes and times of measurement; information for assessment of the

risk of bias. The lead reviewer (AP) will extract the data and any ambiguity/

questions will be discussed with 2nd (JW) and / or 3rd (IM) reviewer. Missing

data will be requested from study authors and / or manufacturers.

Study quality will be assessed using Cochrane collaboration's risk of bias tool

and publication bias by visual inspection of funnel plots (19).

Narrative qualitative evidence synthesis will be provided on aggregate level on

study outcome for their primary and secondary outcome. Qualitative reporting

of evidence will be based on 21 items listed on standards for reporting

qualitative research (SRQR) (20). Total number of patients in the study, study

quality, risk of bias and effect size will be detailed on qualitative evidence

summary.

Meta-analysis

It is authors’ intention to undertake quantitative meta-analysis. If study data

and sample size are sufficient meta-analysis will be performed. Statistical

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significance will be set at 0.05 with p-value <0.05 considered statistically

significant. The primary effect size will be relative risk presented with 95%

confidence interval. The analysis will be based on intention-to-treat where

data available. Study heterogeneity will be measured using I2-statistic

considering values of 50% or higher to reflect considerable heterogeneity

which will be investigated.

Sensitivity analysis

If sufficient number of studies and sample size are available, sensitivity

analysis will be carried out on manic vs. depressive symptoms and

monotherapy vs. adjunctive therapy or different antipsychotic.

Ethical approval: This systematic review does not require ethical approval as data

used here are not individual or private and there will be no primary data collection.

Funding statement: This research received no specific grant from any funding

agency in the public, commercial or not-for-profit sectors.

Acknowledgement: We would like to thank Dr Bonnie Teague, Research Manager at

Norfolk and Suffolk NHS Foundation Trust, for her support and encouragement for

this study.

Declarations of interest: AP received conference travel expenses from Janssen. IM

has received speaker honoraria from Astellas Pharmaceuticals. JW received grants

from Lundbeck, personal fees from Shire outside the submitted work.

Authors’ contribution: AP and IM conceived the study. AP drafted the protocol and

registered with PROSPERO. IM helped design the protocol and reviewed protocol.

JW reviewed the protocol. All authors have approved the publication of this protocol.

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