Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review
Duffy et al. Int J Bipolar Disord
Efficacy and tolerability of lithium in treating acute mania in youth with bipolar disorder: protocol for a systematic review
A. Duffy 0 2 3
S. Patten 1
S. Goodday 7
A. Weir 3 6
N. Heffer 5
A. Cipriani 4 8
0 Department of Psychiatry, Hotel Dieu Hospital, Queen's University , 166 Brock Street, Kingston, ON K7L 5G2 , Canada
1 Department of Psychiatry, University of Calgary , Calgary, AB , Canada
2 Department of Psychiatry, Hotel Dieu Hospital, Queen's University , 166 Brock Street, King- ston, ON K7L 5G2 , Canada
3 Mood Disorders Centre of Ottawa, University of Ottawa Health Services , 100 Marie Curie Private, Suite 300, Ottawa, ON K1N 6N5 , Canada
4 Department of Psy- chiatry, Oxford University , Oxford , UK
5 Oxford University , Oxford , UK
6 Department of Epidemiology, University of Ottawa , Ottawa, ON , Canada
7 Department of Epidemiology, University of Toronto , Toronto, ON , Canada
8 Oxford Health NHS Foundation Trust, Warneford Hospital , Oxford OX3 7JX , UK
Background: Epidemiological, clinical, and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence. Moreover, clinically significant manic symptoms may occur even earlier, especially in children at familial risk. Lithium is the gold standard treatment for acute mania in adults, yet to our knowledge, there is no published systematic review assessing lithium treatment of mania in children or adolescents. This is a major gap in knowledge needed to inform clinical practice. Aim: As a working group within the ISBD Task Force on Lithium Treatment (http://www.isbd.org/active-task-forces), our aim is to complete a systematic review of the efficacy, tolerability, and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder. Methods: We will include double- or single-blind randomized controlled trials in patients aged less than 18 years. No restrictions will be made by study publication date or language. Several electronic databases will be searched along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies. Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome. Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts, respectively. Secondary outcomes will include rates of remission, severity of manic symptoms at different time points, and incidence of specific adverse events. Discussion: Findings from this systematic review are critically needed to inform clinical practice. We should not generalize findings from adult studies, as children and adolescents are undergoing accelerated physiological and brain development. Therefore, efficacy, tolerability, and acceptability of lithium treatment of acute mania in children compared to adults may be very different. This systematic review has been registered in PROSPERO (CRD42017055675).
Lithium; Mania; Child and adolescent; Systematic review; Bipolar disorder; Acute treatment
Bipolar disorder (BD) describes a group of heterogeneous
mood disorders (Angst et al. 2004). More than 2% of the
world’s population is affected with the most severe forms
identified by a manic, mixed or hypomanic episode; while
an estimated 5% of the population is affected with milder
spectrum conditions (McDonald et al. 2015;
Merikangas et al. 2007). In addition, relatively high rates of manic
symptoms are reported in child and adolescent
non-clinical populations, which can represent normative variants
rather than precursors to BD unless combined with other
risk factors such as family history (Tijssen et al. 2010a, b).
Bipolar disorder runs in families with an estimated
heritability of up to 80% (Bienvenu et al. 2011; Smoller and
Finn 2003). High-risk, clinical, and population studies
estimate that the peak period for onset of BD is
adolescence and early adulthood (Duffy et al. 2014; Mesman
et al. 2013; Leboyer et al. 2005; Angst et al. 2005a, b). Yet,
it is estimated to take over a decade to accurately
diagnose BD and this delay is associated with devastating
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consequences including school drop-out, economic,
occupational, and interpersonal problems, inappropriate
treatment, substance abuse and chronicity (Ghaemi et al.
2002; Judd et al. 2005). Given that the onset occurs
during a critical developmental period, taken together with
the lag in diagnosis and severity of acute episodes early in
the course, it is not surprising that BD is among the
leading causes of years lived with disability worldwide
(Whiteford et al. 2013). Further, there is a significant reduction
in life expectancy evident already early in the illness
course in adolescent patients attributable to medical
illness, accidents, and suicide (Baethge and Cassidy 2013;
Kessing et al. 2015a; b).
Lithium is the first line or gold standard treatment for
acute mania and prophylaxis of recurrent BD episodes
(both manic and depressive) in adults (Yatham et al.
2013; Grof and Muller-Oerlinghausen 2009). Moreover,
substantial evidence supports that lithium has a specific
anti-suicidal effect with the potential to normalize the
morbidity rate in BD patients (Muller-Oerlinghausen et al.
1992; Cipriani et al. 2013; Baldessarini and Tondo 2008).
Despite the widespread use of lithium in treating BD for
over 50 years, we still know little about the specific
therapeutic mechanisms of action (Malhi and Outhred 2016).
Importantly here, lithium started earlier in the course of
BD may have a higher likelihood of treatment response
(Kessing et al. 2014) and preliminary findings suggest
that lithium may have neuroprotective effects (Malhi
and Outhred 2016; Hajek et al. 2013; Pfennig et al. 2014).
Yet, the effectiveness, tolerability, and acceptability of
lithium treatment in children and adolescents diagnosed
with BD is even less well understood and understudied.
As a result, most guidelines focus on adult patients with
established illness (Yatham et al. 2013; Fountoulakis et al.
2016). Therefore, as part of the ISBD Task Force on
Lithium Treatment (http://www.isbd.org/active-task-forces),
our working group is embarking on a systematic review of
studies to inform efficacy, tolerability, and acceptability of
lithium treatment for acute mania in children and
adolescents diagnosed with BD.
Criteria for considering studies
We will include double- or single-blind randomized
controlled trials where lithium is used in the treatment of
acute manic episodes in comparison with other active
drugs or placebo. In view of the important role for
randomization as a methodological protection against
selection bias and confounding, we will exclude all
quasirandomized studies. Studies that report randomization
but do not report a procedure for random assignment
will be included, as adequacy of randomization will be
quantified in our risk of bias assessment. For trials that
have a cross-over design, we will only consider results
from the first period prior to cross-over.
We will consider all studies including males and females
less than 18 years of age with a primary diagnosis of BD
and experiencing a manic episode, according to standard
diagnostic criteria such as DSM or equivalent. Studies
that defined mania only as scoring above a certain
cutoff on a screening questionnaire will be excluded, as will
studies that defined a manic equivalent as part of a
primary mood dysregulation disorder. We will not apply any
restrictions by treatment setting. We will not consider
concurrent secondary diagnosis of another psychiatric
disorder an exclusion criterion. However, we will exclude
studies recruiting participants with a serious
concomitant medical illness, neurological disorder, diagnosed
intellectual disability, or brain injury.
All interventions could be monotherapy or combined
with other treatments. We will include trials that allow
for rescue medications (as required, short-term,
infrequent use aimed at emergent symptom relief only) as
long as these medications were equally applied among
the randomized arms.
• Efficacy: Difference in response (as defined by a
decrease in score on any validated mania rating scale
of ≥50% from baseline) between lithium and
comparatively treated patients (placebo or other
antimanic agent) at designated time points
• Tolerability: Difference in serious adverse events (e.g.
death, renal failure, diabetes insipidus, clinically
significant ECG changes, toxic rash) between lithium
and comparatively treated patients
• Acceptability: Differences in discontinuation rates
for any reason between lithium and comparatively
• Efficacy: Difference in remission (YMRS (Young et al.
1978) score of ≤12 or equivalent) between lithium
and comparatively treated patients at designated time
• Efficacy: Difference in mean endpoint scores and
change in scores of manic symptoms (as measured by
the YMRS or equivalent)
• Tolerability: Differences in specific side effects
including but not limited to cognitive impairment,
diarrhoea, gastric irritation, nausea,
haematological abnormalities, hypothyroidism,
hyperparathyroidism, polyuria, non-toxic rash, somnolence,
lethargy, thirst, tremor, weight gain
To avoid missing any rare or unexpected side effects, in
the data-extraction phase, we will collect information on
all side effects reported in the included studies and
discuss ways to summarize them post hoc.
Outcomes will be recorded at the following time
points, if reported by individual studies:
• At 4 days (if not available less than 1 week)
• At 1 week (or between 1 and 2 weeks)
• At 3 weeks (or more than 2 and up to 4 weeks)
• At 6 weeks (or more than 4 and up to 8 weeks)
• At 12 weeks (or more than 8 and up to 16 weeks)
Search methods for identification of studies
We will search EMBASE, MEDLINE, PsycINFO,
CINAHL, and the Cochrane Central Register of
Controlled Trials (CENTRAL), the trial databases of
regulatory agencies and the websites of pharmacological
industries for published, unpublished and ongoing
randomized controlled trials. No language or study
publication date restrictions will be applied. See PROSPERO
(CRD42017055675) for full details about the search
strategy, including the text words and keywords that will be
used and the list of websites.
Data extraction and analysis
Two authors (AW and NH) will independently screen
titles and abstracts to identify potentially relevant
studies retrieved by the search strategy. The full text of the
screened studies will be reviewed for inclusion.
Agreement rates on the initial assessments will be reported
using the kappa coefficient. All reasons for excluding
the ineligible studies will be recorded. Any disagreement
will be resolved through discussion or, if required, by
consulting other authors of the review team (AD, SP, AC).
The frequency and nature of all such disagreements will
be recorded in a study log. We will identify and remove
duplicate records and collate multiple reports that relate
to the same study so that each study, rather than each
report, is the unit of interest in the review. We will record
the selection process in sufficient detail to complete a
PRISMA (Moher et al. 2009) flow diagram and a
characteristics of excluded studies table.
Assessment of risk of bias in included studies
Pairs of review authors (AD, AW, SP, SG) will
independently assess the risks of bias for each study using the
criteria outlined in the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins et al. 2011; Higgins
and Green 2011). Any disagreements will be resolved
by discussion with another member of the review team
(AC) and the results of these discussions will be logged.
We will assess the risk of bias according to the following
domains: random sequence generation, allocation
concealment, blinding of participants and personnel,
blinding of outcome assessment, incomplete outcome data,
and selective outcome reporting. We will judge each
potential source of bias as high, low, or unclear.
Intraclass correlation coefficients will be used to quantify the
risk of bias assignments by different reviewers.
Measures of treatment effect
We will calculate the mean difference (MD) or
standardized mean difference (SMD) along with corresponding 95%
confidence intervals (CI) for continuous outcomes. We will
use the MD where the same scale is used to measure an
outcome. We will employ the SMD where different scales
were used to measure the same underlying construct.
We will calculate the relative risk (RR) with
corresponding 95% CI for dichotomous outcomes. We will calculate
response rates out of the total number of randomized
participants. For statistically significant results, we will
calculate the number needed to treat for an additional
beneficial outcome (NNTB) and the number needed to
treat for an additional harmful outcome (NNTH).
For both continuous and dichotomous data, we will
only conduct a meta-analysis if pooling is appropriate;
that is, if the treatments, participants, and the
underlying clinical question are homogenous enough. We will
narratively describe skewed data reported as medians
and interquartile ranges. If meta-analysis is pursued, log
transformation of relative risks will be used to enhance
normality of the estimates. Standard errors will be
estimated from the reported confidence intervals.
Missing dichotomous data
We will calculate responders to treatment and
remitters on a strict intention-to-treat (ITT) basis and we will
include dropouts in this analysis. Where participants
were excluded from a trial before the endpoint, we will
assume that they experienced a negative outcome by
the end of the trial (failure to respond to treatment). We
will examine the validity of this decision in sensitivity
Missing continuous data
When there are missing data and the method of ‘last
observation carried forward’ (LOCF) is used to perform
an ITT analysis, we will use the LOCF data. When only
the standard error or t statistics or p values are reported,
we will calculate standard deviations (SD) according to
Altman and Bland (1996). Where SDs are not reported,
we will contact the authors for these data but, in the
absence of data from the authors, we will borrow SD
from other studies in the review (Furukawa et al. 2006).
We will examine the validity of this imputation by
Assessment of heterogeneity
We will first investigate heterogeneity between studies
by visual inspection of all forest plots. If the 95% CI’s of
the RR’s for each study in the pooled analysis does not
include means of other included studies, we will
investigate potential sources of heterogeneity. We will also
calculate the I2 statistic and will interpret the level of
heterogeneity according to the criteria outlined by the
Cochrane Handbook for Systematic Reviews of
Interventions (2011). We will consider if the importance of the
observed value of I2 depends on (i) the magnitude and
direction of effects and (ii) the strength of evidence for
Assessment of reporting biases
We will assess publication bias and small-study effects
using a funnel plot. We plan to use the test for
funnel plot asymmetry only when at least 10 studies are
included in the meta-analysis. In the event of using a
funnel plot, we will interpret results cautiously using
visual inspection. If we identify evidence of small-study
effects, we will investigate possible reasons for funnel
plot asymmetry including publication bias (Egger et al.
We will calculate the pooled RR with corresponding 95%
CIs for dichotomous outcomes. We will calculate the
pooled MD or SMD as appropriate with corresponding
95% CIs for continuous outcomes. Statistical significance
will be defined as a p value of less than 0.05 and a 95% CI
that does not cross the line of no effect. In forest plots
with two or more studies, we will use a random-effects
model for both dichotomous and continuous variables.
We will adopt the random effects model under these
circumstances because it has the highest generalizability for
empirical examination of summary effect measures in
meta-analyses (Furukawa et al. 2002).
As multiple analyses can lead to false-positive and
falsenegative conclusions, subgroup analyses should be
performed and interpreted with caution. We will conduct
subgroup analyses for primary outcomes comparing
children (up to 12 years) to adolescents (between 13 and
We will explore sensitivity analyses for missing data by
applying worst and best case scenarios (that is, missing
data are assumed either as responder or non-responder
in the corresponding sensitivity analysis). Finally, we will
explore potential additional sensitivity analyses and will
report these post hoc.
Summary of findings table
We will construct a ‘Summary of findings’ table for each
comparison and use GRADE proGDT software and the
principles of the GRADE approach (Atkins et al. 2004)
to assess the quality of a body of evidence based on the
extent to which there can be confidence that the obtained
effect estimate reflects the true underlying effect.
There is a major evidence gap needed to inform clinicians
faced with treating seriously ill youth diagnosed with
BD. Over the past decade, there have been a number of
individual acute mania treatment studies published that
should be systematically reviewed and if possible
findings combined into a meta-analysis. While more,
welldesigned, treatment trials are needed in larger numbers
of BD youth during various phases of the illness, this
systematic review represents an important next step;
summarizing the available data to provide evidence about the
efficacy, tolerability, and acceptability of lithium
treatment of acute mania in youth with a primary diagnosis of
All the authors have contributed to the study design and writing of this
manuscript. All the authors read and approved the final manuscript.
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