42.
STR ATEGIES FOR IMPROV ING R A NDOMIZED
TR I A L EV IDENCE FOR TR EATMENT OF 
BIPOLAR DISOR DER
Ayşegül Yildiz, Juan Undurraga, Eduard Vieta, Dina Popovic,
Sarah Wooderson, and Allan H. Young
INTRODUCTION
Presently approved treatments of bipolar disorder are, for
the most part, uniformly unable to address the underlying
etiology (Baldessarini, 2013; Yildiz, Guleryuz, Ankerst,
Ongur, & Renshaw, 2008). Yet contemporary era has wit-
nessed furthermost scientific understanding of the patho-
physiological mechanisms underlying bipolar disorder
and has led to investigations of specific molecular targets
and their neural correlates (Machado-Vieira et  al., 2010;
Mathew, Manji, & Charney, 2008). However, despite
substantial investment for development of target-specific,
receptor-oriented central nervous system (CNS) therapeu-
tics, including the ones for bipolar disorder, a very limited
number of the investigated compounds have survived to
launch in recent years (Hoertel, de Maricourt, & Gorwood,
2013; Kemp et al., 2010). This result does not seem solely to
be due to failure of the underlying rationale or ineffective-
ness of the candidate compounds, which carried them to
Phase I  trials but also increased noise encountered in the
context of randomized controlled trials (RCTs). For CNS
therapeutics only, failure rates at Phase II stage reach 50%,
which is about 15% more than the previous decade (Hurko
& Ryan, 2005; Kemp et  al., 2010; Mallinckrodt, Zhang,
Prucka, & Millen, 2010; Tarr, Herbison, de la Barra, &
Glue, 2011). Considering $15,000 cost per subject for a
Phase II or III trial, it can be appreciated why such high
failure rates may discourage investment in CNS drug devel-
opment research (Kemp et  al., 2010; Kobak et  al., 2010).
From the business perspective, the worst scenario (failure
in Phase III of compounds that appeared to work in Phase
II) is increasingly common (Vieta et  al., 2014). Clearly,
59 9
addressing the methodological obstacles that are impeding
progress in this critical sector of therapeutic development
is warranted.
Regulatory agencies such as the US Food and Drug
Administration (FDA) and the European Medicines
Agency have taken the position that a true appreciation
of an intervention against a major psychiatric illness such
as schizophrenia, depression, and bipolar disorder is only
possible by employment of a placebo-controlled design
(Alphs, Benedetti, Fleischhacker, & Kane, 2012). This
perspective has had a tremendous impact on drug devel-
opment for these common psychiatric disorders (Alphs
et  al., 2012). For instance, more than two-thirds of the
available evidence on antimanic, antipsychotic, and anti-
depressant treatments are against placebo (Kirsch, 2009;
Leucht, Cipriani, et al., 2013; Sidor & MacQueen, 2011;
Yildiz, Vieta, Leucht, & Baldessarini, 2011). This may
partially be due to the requirement of the drug-regulatory
authorities but is also due to preferences of the pharma-
ceutical industry for testing their new compounds against
placebos rather than an active comparator, since the latter
necessitates truly more efficacious drugs (Leucht, Heres,
& Davis, 2013). Obviously, restricting progress in phar-
macology to superiority studies would seriously restrict
progress in other matters such as improved safety or tol-
erability (Vieta & Cruz, 2012), but the use of placebo
as the only suitable comparator for registration studies
is taking the field to a no-end road. Difficulties in con-
ducting placebo-controlled trials for clinically challeng-
ing severe mental disorders with frequently encountered
symptomatic exacerbations have likely instigated distinct
research populations. The predominantly profit nature of
funding with predictable pressure for speedy completion
with positive outcomes might have further contributed to
the formation of such exclusive trial populations. These
placebo-controlled trials-compatible patients are likely to
be at the least severe end of the disease spectrum, respond
to placebo, and increase attention provided in a research
context via the so called “Hawthorne’ effect.” A popula-
tion enriched for placebo responders and deprived for true
drug responders would lead to shrunken drug–placebo
contrasts, which in turn would lead to larger sample sizes
and a greater number of study sites and increased vari-
ance as well as noise. Such a vicious cycle may be oper-
ating since cumulative introduction of “me too” drugs
and have led to recent “anti-psychopharmacology” public
acts fostered in some scientific reviews (Kirsch, 2009).
Considering published, as well as FDA registered and
unpublished RCTs, such critical reviews have for instance
claimed trivial effect of antidepressant drugs (Kirsch,
2009). In interpretation of such critical evidence synthe-
sis reports, one should take into account the potential
effect of failure trials, which have typically failed to detect
the true treatment contrasts; potential mediator effect of
disease severity; and nature of source data attained in the
context of RCTs involving distinct research populations
with milder forms of disease presentations. In the context
of RCTs it has been previously documented those patients
with severer forms of disease manifestation were more
likely to benefit from drug treatment (Kirsch, 2009).
The real-world clinical samples on the other side, for the
most part, uniformly involve patients with higher symp-
tomatic severity so would likely to be enriched for drug
responders. However, due to difficulties in conducting
placebo-controlled experiments in such patients, clini-
cal trials are typically left to patients with milder disease
forms. Indeed, for severe mental illnesses, the RCTs set-
tings may better be perceived as simulation environments;
and evidence synthesis reports based on numeric data
attained in these circumstances need to be translated to
the actual life settings. Further, sometimes even a small
actual treatment effect experienced in the real-life set-
tings may have magnified impacts, as in the critical clini-
cal positions involving the line between life and death or
delusional acts and insight (Leucht, Hierl, Kissling, Dold,
& Davis, 2012). Recent evidence indicates that, as with
schizophrenia, there is accelerated aging in bipolar dis-
order with a consequent shortening in life expectancy of
10 to 13.6 years relative to the general population of same
age (Chang et al., 2011; García-Rizo et al., 2014; Laursen,
2011). Evidence also indicates that effective treatment
6 0 0   •   S E C T I O N I V:   F U T U R E R E S E A R C H
of bipolar disorder is not only important for alleviation
of symptomatic exacerbations but also for protection
against premature death associated with medical causes
related to disturbed immune responses and increased
systemic oxidative stress, as well as suicide (Ahrens et al.,
1995; Cipriani, Hawton, Stockton, & Geddes, 2013;
Drexhage et al., 2011; Leboyer et al., 2012). Considering
longitudinal course and lifetime consequences, observed
drug–placebo contrasts gain even greater appreciation.
However, as with other major psychiatric disorders, there
is certainly much room for development of new therapeu-
tics with robust target specific effects and no or minimum
undesired effects for treatment and prophylaxis of bipo-
lar disorder. For achieving this goal, identification of the
methodological obstacles in design and conduct of RCTs
is absolutely warranted.
PL AC E B O E F F EC T V E R S US
PL AC E B O R E S P ONS E
By definition, the placebo effect engulfs the psychobio-
logical phenomena attributable to the placebo, which
is triggered via the perception or the symbolic mean-
ing of the treatment (Alphs et  al., 2012; Kirsch, 2009;
Raz, Zigman, & de Jong, 2009). Placebo-like effects may
also occur without administration of an actual placebo,
highlighting the central role of expectation and sugges-
tion in placebo-related phenomena. Some effects, espe-
cially relating to the immune and endocrine systems,
are due to conditioning types of processes. For example,
Benedetti (2009) discusses studies involving rats show-
ing that a flavored liquid had immunosuppressant effects
after being repeatedly coadministered with an immuno-
suppressant drug. Likewise, administration of a placebo
with patient expectation of pain relief typically activates
the endogenous opioid system. Conversely, administer-
ing active analgesics via hidden administration—that is,
without the patient’s awareness—significantly reduces
their effectiveness (Benedetti, 2009; Raz et  al., 2009).
Another approach to the placebo effect is associated
with the context surrounding the medical encounter
(Moerman, 2002). This “meaning model” attempts to
explain why red placebos stimulate whereas blue place-
bos calm, why more placebos work better than few, and
why more expensive placebos work better than cheaper
ones. Psychological and behavioral evidence points to
the powerful and unique role of suggestion and expec-
tation in eliciting placebo effects (Benedetti, 2009; Raz
et al., 2009).
 Placebo response, on the other hand, designates the
improvement observed in the placebo arm of a clini-
cal trial, which is produced by the totality of the placebo
biological phenomenon combined with other potential
factors contributing to symptom amelioration, such as pas-
sage of time, spontaneous remission, or natural history of
the disorder, regression to the mean, biases, geographical
and cultural factors, and/or judgment errors (Alphs et al.,
2012; Kirsch, 2009; Raz et al., 2009; Vieta, Pappadopulos,
Mandel, Lombardo, 2011). The difference between the
placebo response and improvement in a no-treatment
control group can be interpreted as the placebo effect
(Kirsch, 2009).
As with the actual drug effect, genotype and pheno-
type related personal codes might determine individual
tendencies for the placebo effect. Since expectation and
anticipation-based responses are in action, a clear level of
consciousness and insight should be preserved for the phe-
nomenon of actual placebo effect. Given that executive func-
tions such as insight, judgment, expectation, and anticipation
would often be disturbed in patients experiencing severe men-
tal illnesses, a true placebo effect would hardly be attainable
in such patients. Consequently, as also indicated in the previ-
ous section, patient populations with more severe expressions
of such mental illnesses would likely to be enriched for drug
response. Given ethical and clinical concerns, this aspect of
true placebo effect that is related with disease severity cannot
be fully encountered in the context of clinical trial settings.
However, efforts for achieving better simulation environ-
ments in the context of clinical trials can be optimized.
A wider window for manipulation of the placebo-associated
responses can be encountered through the effect of time on
the establishment of partial or full remissions, regression to
the mean, biases, and judgment errors.
C L I N IC A L T R I A L S OF   B I P OL A R   M A N I A
E F F EC T S I Z E FOR A N T I M A N IC
T R E AT M E N T S R E L AT I V E TO  trials in schizophrenia, substantial placebo-associated
OT H E R M E DIC A L I L L N E S S E S
Effective treatments of acute mania yield an absolute dif-
ference in responder rates of 17% and a standardized mean
difference (SMD), as Hedges’ g based effect size of 0.41
(Yildiz, Vieta, Leucht, et al., 2011), which is comparable to
corresponding values of 18% and 0.51 for second-generation
antipsychotics in the acute treatment of schizophrenia
(Leucht, Arbter, Engel, Kissling, & Davis, 2009). In a
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   6 01
recent mega-analysis considering 94 meta-analytic reports
of 48 drugs in 20 medical diseases and 16 drugs in 8 psy-
chiatric disorders, effect sizes computed for psychotropic
agents were compared to general medical drugs (Leucht
et al., 2012). This analysis revealed a pooled SMD of 0.54
for antihypertensive treatments; 0.41 for antimigraine
treatments; 0.87 for fasting glucose and 0.27 for mortality
with antidiabetic treatments; 0.22 for antibiotic treatments
of otitis media; 0.44 for treatments of ulcerative colitis;
0.36 for treatments increasing ventilatory volume; and 0.20
for prevention of exacerbations in chronic obstructive pul-
monary disease. The authors concluded that antimanic or
antipsychotic drugs are not generally less efficacious than
average medical drugs (Leucht et  al., 2012). Nonetheless,
clearly there is much room for the development of more
effective therapeutics with better efficacy and safety profiles
for patients with bipolar disorder.
I S PL AC E B O R E S P ONS E R I S I NG
I N A N T I M A N IC T R E AT M E N T T R I A L S?
Increasing placebo response is a major concern for anti-
psychotic drug trials (Alphs et  al., 2012; Kemp et  al.,
2010; Leucht, Heres, et  al., 2013). In a comprehensive
meta-analysis of 50 placebo-controlled antipsychotic
drug trials of schizophrenia spectrum disorders con-
ducted since 1970, Agid and colleagues (2013) reported
that placebo response has increased over the past few
decades, especially from 1993 to 2010. In this work, a
standardized mean change (SMC) of  –0.33 (95% con-
fidence interval [CI] =  –0.44 to  –0.22) from baseline
to endpoint for the placebo group was reported. The
authors also reported that larger placebo mean improve-
ments were associated with smaller drug–placebo differ-
ences. In a more recent multiple treatments meta-analysis
of antipsychotic drug trials for acute treatment of schizo-
phrenia exact same SMD of –0.33 (95% credible inter-
val [CrI] =  –0.43 to  –0.22) for the placebo-associated
improvements was computed (Leucht, Cipriani, et  al.,
2013). Similar to the findings with antipsychotic drug
mean improvements were documented also for the tri-
als of bipolar mania. Two recent reviews, one involv-
ing a total of 20 single-agent and add-on studies (Sysko
& Walsh, 2007), and the other with 38 single-agent
studies (56 drug-placebo contrasts) indicated a
placebo-associated response rate of 31% in trials of bipo-
lar mania (Yildiz, Vieta, Tohen, & Baldessarini, 2011).
Both reviews reported a secular trend for rising placebo
effects for industry-supported studies (Sysko & Walsh,
2007; Yildiz, Vieta, Tohen, et al., 2011).
P OT E N T I A L E F F EC T MODI F I E R S
I N R A N D OM I Z E D CON T ROL L E D T R I A L S
A N D S T R AT E G I E S TO DI M I N I SH T H E I R
U N FAVOR A BL E I M PAC T S
In this section each of the below factors are evaluated as poten-
tial effect modifiers in the context of RCTs of acute mania.
• The number of study sites
• Sample size
• Gender
• Age
• Psychotic and mixed features
• Trial completion rates
• Baseline disease severity
• Quality of ratings
• Study and illness duration
• Financial incentives affecting investigators and candi-
date patients
A recent meta-regression analysis investigating the phe-
nomenon of placebo response in bipolar mania established
that higher number of collaborating study sites was strongly
associated with greater placebo-induced improvements (mean
difference [MD]: 38 trials; ß = –0.11, 95% CI: –0.15 to –0.06,
z = –4.67, p < .0001) and diminished drug–placebo contrasts
(SMD as Hedges’ g: 48 trials; ß = 0.007, 95% CI: 0.003 to
0.01, z = 3.79, p = .00015; Yildiz, Vieta, Tohen, et al., 2011).
A finding missed in previous reviews owing to consideration
of placebo and drug arms conjointly in the same regression
model (Tarr et al., 2011). The finding indicating the number
of study sites as an effect mediator has recently found sup-
port in antipsychotic treatment trials of schizophrenia spec-
trum disorders (Agid et  al., 2013). In this comprehensive
meta-analysis, the authors detected a significant increase in
placebo response over the past few decades and explained this
temporal effect by an increase of the number of sites per trial
accompanied by a decrease in the number of academic sites
(Agid et al., 2013; Leucht, Heres, et al., 2013). In light of these
findings, we can propose the number of study sites as a criti-
cal factor contributing to the substantial noise encountered in
the context of placebo-controlled RCTs.
6 0 2   •   S E C T I O N I V:   F U T U R E R E S E A R C H
Large studies do not only involve higher number of study
sites but also large patient samples. For bipolar mania the
meta-analysis described previously indicated that also a large
sample size was associated with greater placebo-associated
improvements (MD: 38 trials; ß = +0.06, 95% CI: 0.04 to
0.08, z = 6.47, p < .0001) and smaller drug–placebo con-
trasts (SMD as Hedges’ g: 48 trials; ß = –0.001, CI: –0.003
to  –0.0004, z =  –2.63, p  =  .008; Yildiz, Vieta, Tohen,
et al., 2011). In a database of 27 acute schizophrenia stud-
ies conducted between 1997 and 2008 it was reported that
for each 1-point increase in the placebo mean change, the
drug–placebo contrast decreased 0.4 points (Mallinckrodt
et al., 2010). The authors also reported that as the percent-
age of patients randomized to placebo increased, mean
placebo-induced improvements decreased (Mallinckrodt
et al., 2010). In another meta-analysis of antipsychotic tri-
als of schizophrenia, Agid and colleagues (2013) reported
that greater placebo response was associated with the lower
percentage of patients assigned to placebo when only stud-
ies published since 1998 were considered. However, the
association was lost when the entire set of trials were con-
sidered (Agid et al., 2013). These opposing effect directions
documented for the RCTs of bipolar mania versus schizo-
phrenia may result from differences in trial, patient, and/
or disease characteristics. For instance, for schizophrenia
trials the percentage of patients randomized to placebo
was reported in the range of 20% to 33% (Mallinckrodt
et al., 2010), while it was about 47% for the RCTs of bipo-
lar mania (Yildiz, Vieta, Tohen, et al., 2011). As mentioned
earlier, current trends in the RCTs settings by compelling
speedy completion and positive outcomes are likely to result
in larger and larger trials yielding smaller contrasts through
increased variance and noise.
Trial participants’ age was also reported as an effect
mediator in the context of placebo-controlled RCTs of
bipolar acute mania (Yildiz, Vieta, Tohen, et  al., 2011).
This meta-regression analysis has documented that younger
mean age of trial population was associated with lesser pla-
cebo effects (MD:  36 trials; ß  =  +0.92, 95% CI:  0.33 to
1.15, z = 3.07, p = .002) and greater drug–placebo contrasts
(SMD as Hedges’ g: 46 trials; ß = –0.09, CI: –0.13 to –0.04,
z = –4.03, p = .00006; Yildiz, Vieta, Tohen, et al., 2011).
Again, direction of effect was opposite to the antipsychotic
trials of schizophrenia, for which younger age was associ-
ated with higher placebo responses (Agid et al., 2013).
Similarly, male gender was found to be associated
with fewer placebo responses (MD:  35 trials; ß =  –0.18,
95% CI: –0.29 to –0.06, z = –3.04, p = .002) and greater
drug–placebo contrasts (SMD as Hedges’ g:  46 trials;
ß = +0.02, 95% CI: 0.007 to 0.03, z = 3.49, p = .0005) in the
context of bipolar mania trials (Yildiz, Vieta, Tohen, et al.,
2011). Gender effect in schizophrenia trials is questionable,
as the most comprehensive recent review did not detect any
sign of gender influence on the placebo-associated responses
(Agid et al., 2013), while an earlier review had documented
a 3-point increase in the mean placebo-associated improve-
ments for each 10% increase in the female trial populations
(Mallinckrodt et al., 2010). While disease-based specificity
of the effect is questionable, given trial-level protection by
randomization one would expect equal gender distribution
in the treatment arms. Yet, as documented, nonsignificant
differences in the distribution of male and female genders
in the corresponding study arms yield a significant media-
tor effect when considered all together in the context of
placebo-controlled RCTs. If such an effect can be verified
in future regression models, trial designs for acute mania
may call for more male participants but with a balanced
study arm-based allocations.
Another proposed factor operating in the proposed
vicious cycle is disease severity. Rising ethical standards and
concerns on randomizing severe patients to placebo might
have caused enrolment of progressively milder patients
into clinical trials over time. The largest standard pairwise
meta-analysis on antimanic treatment trials indicated that
not placebo- but drug-associated improvements were pre-
dicted by increased disease severity (46 trials; ß  =  +0.26,
95% CI: 0.13 to 0.40, z = 3.80, p = .0002; Yildiz, Vieta,
Leucht, et  al., 2011). The finding, being specific to active
drugs, supported by the previous meta-analytic models,
cannot solely be explained by a regression to the mean,
but rather suggest a pharmacological response component
in patients with more severe forms of bipolar mania (Tarr
et al., 2011; Yildiz, Vieta, Leucht, et al., 2011). In that sense,
it supports the assumption that patient populations expe-
riencing more severe forms of mania would be enriched
for drug responders. Another factor related to severity of
manic episode is the presence of psychotic features. Impact
of psychotic features was also specific to active drugs
(MD: 40 trials; ß = +0.10, 95% CI: 0.06 to 0.15, z = 4.22,
p  =  .00002), with the effect being more influential, as it
was also reflected on the enhanced drug–placebo contrasts
(SMD as Hedges’ g:  40 trials; ß  =  +0.85, 95% CI:  0.43
to 1.28, z = 3.91, p = .00009; Yildiz, Vieta, Tohen, et al.,
2011). In contrast with the effect of psychosis, another
disease-specific modulator: mixed features decreased both
drug-response and drug–placebo contrasts (MD: 45 trials;
ß = –0.07, 95% CI:–0.12 to –0.03, z = –3.26, p = .001; SMD
as Hedges’ g: 45 trials; ß = –0.59, 95% CI: –0.99 to –0.19,
z = –2.92, p = .004, respectively; Yildiz, Vieta, Tohen, et al.,
2011). Neither presence of psychotic- nor mixed-features
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   6 0 3
had any impact on responses to placebo treatment. The
sensitivity and specificity of the observed effects, as well as
clinically distinct features of pure mania versus mania with
mixed features, may validate consideration of patients with
prominently mixed features, exclusively in independent tri-
als. However, given recent modifactions in description of
mixed features this finding needs to be replicated in future
antimanic treatment trials. Given arm-based specificity of
the effect, it is not surprising that a previous meta-regression
model considering all study arms conjointly could only
detect a trend toward a poorer outcome associated with
mixed states (Tarr et al., 2011). Based on above summarized
evidence, we may suggest inclusion of patients with mod-
erate to severe forms of mania with or without psychotic
features but with no prominent depressive components.
Special care should be given to avoid patients who might
have already entered the natural waning stage for the cur-
rent episode as well as treatment-refractory patients.
Another factor associated with lower drug–placebo
contrasts in bipolar mania trials was the higher dropout
rates (Yildiz et  al., 2011). If the drug-associated benefit
and the resulting treatment effect is being modulated by
disease severity either in the form of high baseline scores
or presence of psychotic features, manic patients need to be
exposed to the active drug long enough for accomplishment
of the brain’s adaptive response to drug-induced pharma-
cological alterations. The meta-analysis over 56 compari-
sons found that higher trial completion rates in drug arms
were associated with both greater drug-associated benefit
and drug–placebo contrasts (MD: 46 trials; ß = 0.08, 95%
CI:  0.04 to 0.13, z  =  3.99, p  =  .00007; SMD as Hedges’
g: 46 trials; ß = 0.006, 95% CI: 0.002 to 0.009, z = 2.86,
p  =  .004, respectively; Yildiz, Vieta, Tohen, et  al., 2011).
Considering that RCTs of acute mania involve already
short study durations (three or four weeks), high rates of
early dropouts are likely to mask actual magnitude of the
true drug effects.
Evidence indicates that younger bipolar patients with
short illness durations would be more likely to respond to
pharmacologic treatment and less likely to respond to pla-
cebo (Yildiz, Vieta, Tohen, et  al., 2011). Since diagnosis
of bipolar disorder can technically be made only after the
establishment of the first manic episode and an accurate
documentation of age onset for the first mood episode is
often barely obtainable, we did not attempt to extract data
for illness duration. Nevertheless, present findings on the
age effect as well as the clinical impression for obtaining
better treatment responses in patients with more recent dis-
ease onset support the notion that younger patients with
shorter illness durations may constitute better research
samples with enhanced treatment contrasts. If this notion
can find further support, a new illness duration related
inclusion criterion may be considered.
Another potentially important factor mediating
drug–placebo contrasts is the quality of ratings:  both for
baseline- and outcome-assessments. A recent methodologi-
cally sound study compared effect of site-based and cen-
tralized ratings on patient selection and placebo response
in subjects with major depressive disorder (Kobak et  al.,
2010). That study established that 35% of the included
subjects would not have been eligible to enter the study if
the centralized rater’s score was used to determine study
entry. Further, the mean placebo change for the site-raters
(~7.5) was significantly greater than the mean placebo
change for centralized raters (~3.18, p < .001; Kobak
et  al., 2010). Although there is no published study inves-
tigating this issue in terms of manic symptom assessments,
baseline score inflations, as well as expectancy effects (the
tendency to see improvement over time), site-based rat-
ings are likely to increase placebo-associated responses
and diminish drug–placebo contrasts for the RCTs of
bipolar mania as well. Given natural vulnerability of
scale-based measurements, such inflations in baseline-
and/or outcome-assessments can be easily mediated by the
site investigators, site nurses, as well as study patients. For
instance, the so-called “professional” patients seen in the
catchment area of often-used trial sites might exaggerate
their symptoms in order to be eligible for a study (Alphs
et  al., 2012). Similarly, site-investigators themselves may
consciously or unconsciously inflate baseline scores in order
to meet patient eligibility requirements, especially when
sites are paid on a per-patient basis. For ensuring quality
of ratings, interrater reliability should be checked at the
beginning and also often during the study conduct. A cen-
tralized rater should synchronously watch the site investi-
gators’ ratings, and patient inclusion should be decided by
their mutual agreement. Manic symptom improvements
should be assessed by standardized use of a common met-
ric such as the Young Mania Rating Scale (YMRS; Young,
Biggs, Ziegler, & Meyer, 1978). Administration of different
instruments with discrepancy in target symptoms, measure-
ment items, and score ranges, may potentially increase vari-
ance and heterogeneity (Yildiz, Vieta, Correll, Nikodem, &
Baldessarini, 2014).
Finally, regulations on investigator payments may have
an impact on the study completion or dropout rates as such
drug-effects and treatment contrasts. In industry-sponsored
trials site investigators are often paid on a per-patient basis
upon completion of one post-baseline evaluation. In such
circumstances investigators may lose their motivation for
6 0 4   •   S E C T I O N I V:   F U T U R E R E S E A R C H
dealing with extremely energy-demanding manic patients
for the subsequent two or three weeks. Considering that
the brain’s adaptive response to pharmacotherapy necessi-
tates longer exposure and previously documented negative
influence of early dropouts on drug-associated responses, as
well as drug-placebo contrasts, we propose a payment strat-
egy facilitating constant investigator motivation through-
out the study. Last but not least, employment of rescue
medications in conduct of acute mania trials may call for
special attention. The protocol-guided use of rescue medi-
cations is usually left to the yard staff since the site investi-
gators are often occasionally on the yard. Given that manic
patients would often cause sleepless and stressful shifts,
the yard staff may tend to employ rescue medications at a
maximum possibly allowed dose and rate. Given that exclu-
sion of benzodiazepines as rescue medications from the
trial protocols is not feasible, their employment by the site
investigators, rather than the yard staff, on an exclusively
as-needed basis may facilitate drug–placebo separation and
reduce the risk of failure trials. Since manic patients often
need constant extra care and timely handling during repeat-
edly encountered crisis, for enabling optimized and timely
site evaluation and crisis management we suggest that the
site investigators to stay on the yard through day and night
shifts during the study conduct. Constant presence of the
site investigators on the yard would not only optimize use
of rescue medications but also award system systematically.
Specific features of the manic syndrome such as inflated
self-esteem, high energy, and increased tendency for plea-
surable activities with diminished or no sleep make com-
patibility with a protocol-guided treatment in an inpatient
unit very challenging both for the patients and staff. For
minimizing early dropouts with limited use of pharmaco-
logical restraints while optimizing patients’ comfort and
compliance, employment of some recreational incentives
with a negotiation-based award-promoting approach may
help them to stay calm in the yard without harming them-
selves or others. Among such incentives may be special per-
missions for immediate family members’ visits to the yard,
occupation with safety-guarded energy-consuming games
or activities, day and night television/video entertainment,
Wi-Fi access, and special meals. One may argue against use
of such recreational activities with concerns on enhanced
placebo responses. However, our experience with the larg-
est proof-of-concept academic trial in a manic patient sam-
ple with a mean syndromal severity of 63% of maximum
possible score by the YMRS and psychotic features accom-
panying at a rate of 67% implied that employment of some
recreational incentives increased study completion rates
and enhanced drug–placebo contrasts (Yildiz et al., 2008).
In contrast, without such sensitive considerations, RCTs
are left to patients with softer or already alleviated forms of
manic syndrome or to the so called “professional” patients,
yielding a group enriched for placebo responders. It is likely
that a research population with more severe forms of manic
syndrome would be enriched for real drug responders, but
we need them to stay in the trial long enough to let the brain
accomplish an adaptive response. The optimum and safe
employment of such award mechanisms can be achieved
only by the constant supervision of the site investigators.
Quality and safety control by an independent monitor may
also be considered. On condition that any indications of
poor patient care and/or study conduct are identified, an
action plan for further training or change of the investiga-
tors or research nurses or safety guards may be considered,
and a central backup team may take position on the site in
the meantime.
CONS I DE R AT ION OF 
A LT E R NAT I V E DE S IG NS
Placebo-controlled RCTs of mania constitute A-plus evi-
dence, and they are actually the designs requested by the
regulatory agencies. While we encourage the aforemen-
tioned approaches for improvement of quality and hopefully
quantity of placebo-controlled RCTs of bipolar mania, in
situations with limited sources alternative trial designs such
as add-on or head to head trials may provide complemen-
tary clinical information if planned appropriately. As in the
case of add-on trials, positive head to head trials designed
for testing noninferiority may serve to provide rationale
for a placebo-controlled monotherapy trial and accumulate
data for future evidence synthesis. Head to head trials prov-
ing superiority over standard treatments might be another
option although this approach, even more so, requires drugs
that are truly more efficacious (Leucht, Heres, et al., 2013).
The use of an early-response/nonresponse paradigm is
another study design worth considering in order to enhance
the selection of true drug responders, who can then par-
ticipate in a double-blind, placebo-controlled discontinua-
tion trial (Alphs et al., 2012; Correll, Malhotra, Kaushik,
McMeniman, & Kane, 2003; Kinon et  al., 2010). This
strategy involves treating all patients with the experimental
drug with or without an active control and then identify-
ing those subjects who have at least a minimal prespecified
level of improvement after two weeks of treatment. Because
such patients represent a group enriched for drug respon-
siveness, they constitute an ideal subgroup to enter into a
double-blind discontinuation study, where, following stabi-
lization, patients are randomized to continued treatment or
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   6 0 5
placebo and time to destabilization is the endpoint (Alphs
et al., 2012; Correll et al., 2003). The assumption underly-
ing such a design would be that the early responders would
include a greater proportion of patients who are truly
“drug responsive,” although it would also include some
proportion of “placebo responders” (Alphs et  al., 2012).
Finally, investigator-initiated, large international trials
to be funded by the National Institute of Mental Health,
the FDA, the Department of Veterans Affairs, European
Union Human Research Programs, and other medi-
cal research agencies by employing adaptive or sequential
treatment strategies involving acute as well as maintenance
phases would provide clinically very useful answers for the
most critical research questions. Improvement of industry-
or academia-initiated placebo-controlled RCTs together
with employment of such alternative designs would likely
change the face of placebo-associated responses, as well as
the magnitude of the observed treatment contrasts in the
trials of bipolar mania.
Finally, improvements in the individual RCTs would
have extended impacts when combined via analytic evi-
dence synthesis approaches. To enable the most informa-
tive and valid future evidence synthesis, each RCT effort
should be registered before conduct and published upon
completion by reporting quantifiable data on all outcome
measures in a standardized manner. Further, by consider-
ing future evidence syntheses, each RCT report should
report on the subgroups, such as those with or without psy-
chotic or mixed features. In addition, outcome measures
should involve important side effects encountered with use
of antimanic drugs, again via a standardized approach: for
example, data on patient’s weight at baseline and end point,
change in glucose or lipid levels, number of subjects who
experience akathisia and those who need anti-Parkinso-
nian drugs, quantifiable data on extrapyramidal side-effect
assessments, and suicidal thoughts or acts. Without accu-
mulation of such data neither considerate evidence-based
clinical decisions nor an evidence-based action plan for
future research investments would be possible.
C L I N IC A L T R I A L S OF 
B I P OL A R DE PR E S S ION
As reported in the previous chapters, available evidence on
bipolar depression (BPD) is strikingly scarce. There are many
possible reasons for this: The first is related to the fact that
many clinicians and researchers have long assumed that
major depressive episodes in bipolar or unipolar disorders
share some common clinical characteristics and treatment
response. This view also explains why antidepressants have
long been the most common clinically employed treatment
for BPD (Baldessarini et  al., 2007). Moreover, this view
explains the limited commercial interest in extending regula-
tory indications of antidepressants beyond “major depression”
and the lack of specific trials aimed to establish antidepres-
sant efficacy for BPD. The second reason may be related to
safety issues. There are concerns that some drugs used to treat
BPD (i.e., antidepressants), might induce mood switching,
suicidality (i.e., suicidal thoughts or acts), or mood destabi-
lization and rapid cycling (Bauer, Beaulieu, Dunner, Lafer,
& Kupka, 2008; Undurraga et  al., 2012). These concerns
have led to routine exclusion of bipolar patients from most
RCTs in major depression in the past 20 years (Undurraga
& Baldessarini, 2012). Those allowing inclusion of patients
with BPD did not usually select or stratify according to
polarity (Geddes & Miklowitz, 2013). The third reason is
related to clinical features of mood disorders (Baldessarini,
2013), which are typically characterized by clinical complex-
ity, daily or weekly fluctuations in mood and behavior, and
high risk of relapse or recurrence. Moreover, some of the
available treatments can even worsen clinical course when
prescribed or when discontinued, especially when discon-
tinued abruptly (Baldessarini, Vieta, Calabrese, Tohen, &
Bowden, 2010). This clinical complexity and lack of available
RCT–based homogenous evidence on the treatment options
for BPD address the importance of establishing standards for
future RCTs with reliable and consistent diagnostic and clin-
ical assessments, as well as outcome definitions. In addition,
not only do the trial design factors have to meet high quality
standards but also the trial conduct, as well as data reporting.
E V I DE NC E ON E F F IC AC Y A N D S OU RC E S
OF OU TCOM E H E T E RO G E N E I T Y
Meta-analytic reports on antidepressant use for BPD are
often weak and inconsistent due to the paucity (involv-
ing only 4 to 12 trials) and substantial heterogeneity of
the available RCTs (Gijsman, Geddes, Rendell, Nolen, &
Goodwin, 2004; Sidor & MacQueen, 2012; Vázquez,
Tondo, Undurraga, & Baldessarini, 2013). For this reason,
their value in the context of BPD at present is highly ques-
tionable, as pointed out in the International Society for
Bipolar Disorders (ISBD) task force report on the use of
antidepressants in bipolar disorder, where the highest level
of evidence was rated as B (Pacchiarotti et al., 2013). The
situation is similar regarding other available treatments of
bipolar depression, such as anticonvulsants, lithium, and
antipsychotics (Cipriani et al., 2013; De Fruyt et al., 2012;
Reinares et al., 2013; Vieta & Valentí, 2013). As reflected
6 0 6   •   S E C T I O N I V:   F U T U R E R E S E A R C H
on the attempts for evidence synthesis, available RCTs for
BPD are for the most part weak, and the methodological
quality of study designs and their reporting is highly het-
erogeneous. A  recently published systematic review ana-
lyzed the methodology used in the individual RCTs of BPD
in the past 20 years (Spanemberg et al., 2012). The authors
included 30 RCTs in their analysis (all of them published
in journals with an impact factor >3) and found striking
results indicating the uneven and, in general, poor quality
of available evidence. For example, almost half of considered
RCTs were conducted with fewer than 50 patients; 70% of
them failed to describe the method used in determining
their sample sizes; 50% did not assess remission of depres-
sion as an outcome (they limited their analysis to response,
usually defined as 50% reduction in a depressive symptoms
scale); half had attrition rates over 20%; and last observa-
tion carried forward analysis was used in only two-thirds
of the published reports (see Table 42.1 for further details).
The observed heterogeneity in BPD trials makes the
comparison between outcomes (e.g., efficacy measures, tol-
erability) for different treatments and placebo difficult, as
there is a lot of statistical noise. Moreover, high variability
is associated with less statistical power (i.e., more false nega-
tive results; Ghaemi, 2009).
I S PL AC E B O R E S P ONS E R I S I NG I N 
A N T I DE PR E S S I V E T R E AT M E N T T R I A L S?
There has been a steady increase in placebo-associated
responses and an accompanying decrease in drug–placebo
contrasts in antidepressant trials over the past three decades
(Khan, Bhat, Kolts, Thase, & Brown, 2010; Undurraga &
Baldessarini, 2012). Further, certain trial characteristics
such as sample sizes or number of study sites were signifi-
cantly associated with the higher placebo responses in the
antidepressant trials (Undurraga & Baldessarini, 2012;
Walsh, Seidman, Sysko, & Gould, 2002). This association
has been observed particularly in the context of unipolar
depression; however, unipolar and bipolar differentiation
has been a matter of large debate in the past century, and
most studies until mid-1980s did not differentiate between
the two (Baldessarini et  al., 2010; Benazzi, 2007; Khan
et al., 2010).
P OT E N T I A L FAC TOR S CON T R I BU T I NG
TO S TAT I S T IC A L H E T E RO G E N E I T Y A N D
NOI S E FOR BI P OL A R DE PR E S S ION T R I A L S
Certain methodological characteristics of BPD trials and
trial participants may contribute to heterogeneity, noise
Table 42 .1.  METHODOLOGICAL QUALITY OF  ITEM EVALUATED/DESCR IBED NO. STUDIES (%)
PUBLISHED R ANDOMIZED-CONTROLLED
TR IALS IN BIPOLAR DEPR ESSION Type of statistical analysis

Only LOCF 20 (66.7%)

ITEM EVALUATED/DESCR IBED NO. STUDIES (%)
LOCF + OC 2 (6.7%)
Follow-up time (weeks)
≤6 9 (30%) Other or unclear 8 (26.7%)

6 to 8 13 (43.3%) Assessed remission

>8 weeks 8 (26.7%) Yes 13 (43.3%)

Placebo use No 17 (56.7%)

Manic switch
Yes 20 (66.7%)
Not assessed or not described 3 (10%)
No 10 (33.3%)
Dropouts (follow-up)
Diagnostic assessment
≤20% 13 (43.3%)
Structured diagnosis (SCID/MINI) 20 (66.6%)
20% to 50% 14 (46,7%)
Semistructured diagnosis 1 (3.3%)
≥50% 2 (6.7%)
Clinical diagnosis only 9 (30%)
Unclear 1 (3.3%)
Washout period
Type of sponsorship for the study
Yes 11 (36.7%)
Corporate sponsored 14 (46.7%)
No 18 (60%)
Sponsored by institutions/foundations/ 10 (33.3%)
Not described 1 (3.3%) government
Inclusion criteria Not declared/unclear/unsponsored 6 (20%)
Cutoff score defined (HDRS, 27 (90%) NOTE: Adapted from Spanemberg et al. (2012).
MADRS, etc.)

Cutoff score is not defined 3 (10%) effect, and lower effect sizes (Henkel et  al., 2012; Khan,
Number of patients (Total) Schwartz, Kolts, Ridgway, & Lineberry, 2007; Schalkwijk,
Undurraga, Tondo, & Baldessarini, 2014; Undurraga &
≤50 14 (46.7%)
Baldessarini, 2012):
50 to 100 5 (16.7%)

100 to 200 3 (10%)

• Trial-durations

>200 to 500 3 (10%) • Involved study arms: placebo versus active comparators

≥500 5 (16.7%) • Number of involved active treatment arms
Sample size calculation • Sample sizes
Described 12 (40%) • Degree of baseline disease severity
Not described or not performed 18 (60%) • Comparability in dosing strategies
BD Subtypes
• Involvement of ethnically distinct patient populations
BD Type I 6 (20%)
• Number of study sites
BD Type II 1 (3.3%)
• Frequency of assessments
Both 18 (60%)
• Employment or length of a wash-out phase via placebo
Unclear 5 (16.7%)
or no treatment

S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   6 0 7
S T R AT E G I E S FOR DI M I N I SH I NG NOI S E A N D
E N H A NCI NG T R E AT M E N T CON T R A S T S
I N BI P OL A R DE PR E S S ION T R I A L S
Pragmatic trials in addition to placebo-controlled
randomized controlled trials
The placebo-controlled, double-blind, parallel-group RCTs
are the gold standard for establishment of efficacy for an
experimental treatment, but they have an important limita-
tion. That is, the patients are highly selected and homoge-
neous and therefore are unrepresentative of the typical bipolar
patients who tend to have multiple comorbidities with hetero-
geneous presentations and are typically on multiple treatments
(Post, 2009). The fact that rate of exclusions for potential
subjects in a RCT is as high as 80% to 90% underscores how
selective RCT patient populations can be (Post, 2010). In
addition, for technical reasons most trials use monotherapy
in their design, which is far from the usual clinical care. This
situation makes outcome generalizability (i.e., external valid-
ity) of these types of studies a difficult and arguable exercise.
On the other hand, they have good internal validity, and valid
conclusions can be made regarding treatment efficacy.
To deal with the problem of generalizability, effective-
ness trials (otherwise known as pragmatic or practical tri-
als) have been proposed (March et  al., 2005). This type
of “clinically useful” oriented design compares clinically
important interventions and allows the inclusion of more
complex patients with comorbid psychiatric problems, as
such being more akin to everyday clinical practice (though
heterogeneity could reduce internal validity). This kind of
design has been used in recent clinically useful studies such
as STAR-D, STEP-BD, and CATIE (Post, 2010). A more
comprehensive description of the problem with generaliz-
ability and judicious consideration of different trial designs
are provided in Chapter 43 of this book.
Bipolar disorder subgroups
Bipolar type I and II have different clinical characteristics
and treatment responses (Judd et  al., 2003; Pacchiarotti
et al., 2013). Consequently, clinical trials of bipolar depres-
sion may either be conducted for a specific bipolar type or
may involve patients with both bipolar subtypes; however,
in such circumstances a subgroup analysis of outcomes
should be well documented.
Evaluation instruments
The most frequently used clinical scales to assess depres-
sive symptom severity and treatment response are the
6 0 8   •   S E C T I O N I V:   F U T U R E R E S E A R C H
Hamilton Rating Scale for Depression (HRSD), the
Montgomery-Åsberg Depression Rating Scale (MADRS),
and the Inventory for Depression Symptomatology
(IDS), which were initially developed to evaluate uni-
polar major depressive disorder. Although the HRSD,
with 23 items, considers atypical features, the HRSD–17
Items, MADRS, and IDS lack sensibility to correctly
estimate “atypical” depressive symptoms such as anergy,
hypersomnia, or hyperphagia, which are common in
bipolar depression and partly encountered also in mixed
manic-depressive states (Baldessarini et  al., 2010).
Moreover, most of them were developed in nonblind stud-
ies of hospitalized patients and are likely to be less sensi-
tive to milder or subsyndromal forms (Tohen et al., 2009).
Another scale recently developed for the dimensional
measurement of bipolar depression is named as the Bipolar
Depression Rating Scale (BDRS), which comprises items
for assessment of atypical depressive and mixed symptoms
(Berk et al., 2007).
Outcome definitions
Bipolar disorder is a complex illness, with variable course
between and within life cycles of affected individuals.
Clinical presentations such as mania, hypomania, depres-
sion, presence of psychotic and/or mixed manic-depressive
features, subsyndromal depressive states, and rapid cycling
course with variable interepisodic functionality and cogni-
tive impairments, make clear-cut outcomes, which would
cover all various forms of disease manifestation and course,
difficult to define. The problem is even more significant if
we consider that many of these clinical presentations can
remit or change both in relation to treatment as well as
spontaneously, as most are time limited.
In the light of this clinical complexity, the definition of
clear-cut outcomes and treatment objectives (i.e., clinically
meaningful outcomes) is mandatory. An expert consensus
and standardization of outcome definitions and terminol-
ogy is essential to make meaningful comparisons across
studies, as well as combined analysis. Some commonly used
outcomes in BPD trials based on available evidence and
expert consensus are defined next (Martinez-Aran et  al.,
2008; Rush et al., 2006; Tohen et al., 2009):
R E S P ONS E
Response is typically defined as ≥50% reduction in the
initial depression severity scores, as commonly measured
via the HRSD, MADRS, IDS, or BDRS. It is a clinically
useful definition, used to indicate whether to continue
with the same drug, stop and change treatment, or adjust
doses. The main problem of response is that it greatly
depends on the baseline measure of symptom severity,
and regression to the mean may contribute to an invalid
impression of symptomatic improvement (Fava, Evins,
Dorer, & Schoenfeld, 2003). Importantly, a time criterion
in its definition should be employed to avoid misinterpre-
tations by random mood fluctuations (two to four weeks
has been recommended by a recent ISBD task force on
the course and outcome nomenclature in bipolar disor-
ders; Tohen et al., 2009). In addition, during assessment
of response in the context of BPD trials, manic symp-
toms should also be evaluated using standardized scales
to demonstrate that no switching or manic worsening has
occurred, which would invalidate response as a clinically
significant outcome.
R E M I S S ION
Remission is typically based on the posttreatment depres-
sion severity scores. An upper limit for the depression score
is defined under which the patient is defined as remitted
(often if sustained for a period of time). Remission implies
that the signs and symptoms of depression are absent
or nearly absent. Differentiating between response and
remission is important, as a patient could respond to a
treatment without remitting (i.e., patients with residual
depressive symptoms). These patients (responders but
not remitters) experience more psychosocial impairment
and have a higher likelihood of recurrence (Thase, 2003;
Zimmerman et al., 2004). The definition of remission (i.e.,
cut-off scores and time intervals) is still a matter of debate.
Unsurprisingly, lower cut-offs in depression severity rating
scales scores have been associated with better functional-
ity and fewer recurrences in depression (Zimmerman
et al., 2004). Remission cut-offs with the most commonly
used depression rating scales have been suggested by
expert panels (Rush et al., 2006; Tohen et al., 2009). One
of the main limitations of this concept is that it may not
reflect the quantitative change in symptoms (i.e., patients
who enter a study with low scores could have little change
in their symptoms and still be counted or classified among
the remitters; Tohen et  al., 2009). Remission has impli-
cations for functional outcome, prognosis, and course
(Zimmerman et al., 2004); as such, it should be employed
as a primary outcome in BPD trials. Nevertheless, func-
tionality should be measured as a separate outcome, as
symptomatic remission in bipolar depression is not nec-
essarily associated with a return to premorbid day-to-day
functioning (Tohen et al., 2009).
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   6 0 9
R ECOV E RY
Recovery implies remission for an extended period of time,
such that the possibility of relapse or roughening is no lon-
ger a concern and another affective episode is unlikely to
occur in the near future. (The Diagnostic and Statistical
Manual of Mental Disorders [fifth edition] defines it as two
months, the same as the 2009 ISBD task force, which rec-
ommends 8 weeks as the sustained remission criteria).
R E L A P S E A N D R ECU R R E NC E
Both concepts imply the clinical manifestation of the epi-
sode within the predefined time limits. The definition of
relapse and recurrence depends on the natural course of
the illness (in this case, the bipolar depressive episode).
The ISBD has defined relapse as the early return of the
syndrome (≤ 8 weeks), that is, before recovery, and recur-
rence as a late return of the syndrome (>8 weeks)—in other
words, during or after recovery.
S W I TCH I NG
The course of illness for a bipolar patient may involve
immediate change or switching to the opposite pole (i.e.,
depression to mania or vice versa) or a return to a normal
mood state (i.e., euthymia) prior to the next episode. Even
though some drugs could induce switching, the attribu-
tion of treatment as the cause of this complication could
be misleading as it could also correspond to the natural
course of the illness. Tohen and colleagues (2009) have
proposed the nomenclature “treatment-emergent affec-
tive switch” (TEAS) to avoid attributing causality and
propose a definition of definite TEAS if occurring in less
than eight weeks. In addition, they propose including
the specific treatment if the switch emerges within less
than two weeks from the beginning of treatment (e.g.,
antidepressant-associated TEAS).
S U B S Y N DROM A L
The term subsyndromal is used to describe patients who
fail to meet the full diagnostic criteria for a mood episode.
Subsyndromal symptoms are associated with worse social
and occupational functioning and may increase the risk of
relapse (Judd et al., 2008; Marangell, 2004). Considering
their prognostic relevance, subsyndromal symptoms should
be measured. However, the symptom severity scales for
depression have strong limitations regarding this point, as
discussed later.
Table 42 .2 .  R ECOMMENDATIONS FROM THE R A PI D C YC L I NG
INTER NATIONAL SOCIETY FOR BIPOLAR
DISORDERS TASK FORCE R EPORT ON THE
Rapid cycling was originally described by Dunner and
NOMENCLATUR E OF COURSE AND OUTCOME Fieve (1974), who arbitrarily defined it as patients pre-
IN BIPOLAR DISORDERS senting four or more distinct episodes in one year. It has
prognostic importance, as it has been associated with more
CUANTIFICATION
severe depressive episodes, poorer response to treatment,
(SCOR E, W EEKS,
ITEM MEASUR E PERCENTAGE) worse functioning, higher substance abuse comorbidity,
and greater suicidal risk (Cruz et al., 2008). Clinical trials
Symptomatic HDRS, MADRS,
Response IDS, BDRS % improvement
aimed at evaluating a rapid cycling pattern should employ
an adequate extension phase.
<25%, 25–49%,
50-74%, 75–100%

Symptomatic HDRS-17 ≤5 or ≤7 points PR E D OM I NA N T P OL A R I T Y

Remission
Predominant polarity is defined as patients having at
MADRS ≤5 or ≤7 points least two-thirds of their lifetime episodes at one polar-
ity or the other (Colom, Vieta, Daban, Pacchiarotti, &
BDRS ≤8 points
Sanchez-Moreno, 2006), that is, either predominantly
Recovery Time (weeks) Remission ≥8 weeks depressed or predominantly manic. This course speci-
Relapse Time (weeks) New episode <8weeks fier has strong prognostic value, especially relevant to
from remission long-term therapeutic decisions and prediction of outcome.
Predominant depression has been associated with depres-
Recurrence Time (weeks) New episode ≥8weeks
from remission sive or mixed onset, occurrence of more mixed episodes,
rapid cycling course, accompanying psychotic features, and
Subsyndromal HDRS-17 8 to 14 points higher suicidal risk (Baldessarini et al., 2012).
Depression

MADRS 8 to 14 points
F U NC T IONA L OU TCOM E S
BDRS 9 to 16 points
Bipolar disorder can have important consequences in social,
Predominant Depressive 2/3 total episodes cognitive, and occupational functioning. These functional
polarity episodes being depressive
deficits have been traditionally associated with affec-
TEAS tive episodes but may also present during subsyndromal
states and even during euthymia (Jaeger & Vieta, 2007).
Definite & 2 consecutive Full episode ≤ 2 weeks
treatment specific days (>50% time As previously stated, better functionality has been associ-
each day) ated with symptomatic remission, but remission does not
mean returning to a premorbid state of functioning, hence
Definite 2 consecutive Full episode ≤ 8 weeks
days (>50% time it should be measured as a separate outcome. There is a pau-
each day) city of methods for measuring disability. Some of the most
important ones are described next.
Likely 2 consecutive (>2 symptoms +
days (>50% time YMRS >12) ≤ 12 The recently developed Functioning Assessment Short
each day) weeks Test measures six domains of functioning (autonomy,
occupational and cognitive functioning, financial issues,
Possible 2 consecutive (change mood or
days (>4 hrs each energy + YMRS >8) ≤ interpersonal relationships, and leisure time) and may be a
day) 12 weeks good instrument for clinical and research settings, since it
is brief, has high reliability, and is intended specifically for
Unlikely Fleeting > 16 weeks
symptoms. bipolar patients (Rosa et al., 2007). In addition, the World
Environmental Health Organization designed a tool aimed at identify-
or exogenous
contribution
ing and classifying relevant domains of human experience
affected by health conditions (Ayuso-Mateos et al., 2013).
NOTE: Adapted from Tohen et al. (2009).
The International Classification of Functioning, Disability

610   •   S E C T I O N I V:   F U T U R E R E S E A R C H
and Health has two core sets especially developed for bipo-
lar disorder, which describe illness-associated functional
problems (personal and environmental factors). Its main
limitation is that it lacks validation in clinical settings.
Another relevant tool is the World Health Organization
Disability Assessment Schedule, which evaluates differ-
ent domains of functioning and is a helpful research tool,
although it may be too long to use in daily clinical practice
(World Health Organization, 2013).
DATA A N A LY S I S A N D R E P ORT I NG
OU TCOM E A NA LY S I S A S  of errors, researchers should choose one or a few primary
I N T E N T ION TO T R E AT
A N D DROP OU T R AT E S
After defining the primary and secondary outcomes to be
measured, the strategy for their analysis should be decided.
Completer analyses have major limitations that include loss
of power and loss of initial randomization as a consequence
of dropouts (i.e., people who do not complete the study)
not being aleatory (e.g., dropouts in one group as a conse-
quence of adverse effects of medication or lack of efficacy).
Therefore, samples of remaining subjects (i.e., completers)
might be unrepresentative (Tierney & Stewart, 2005).
Intention to treat analysis includes analysis of data of
all randomized participants, irrespective of how much of
the treatment they received. In other words, it evaluates
the treatment offer. This is intended to equalize the poten-
tial confounding factors for the entire sample but presents
problems too. To account for incomplete data in this type
of analysis, one of the most common strategies is to use the
last observation carried forward (LOCF), where endpoint
data is substituted with previous results. The LOCF impu-
tation method has limitations as well, because it assumes
that dropout is not related to treatment or to outcome
and that a subject who discontinues treatment would have
retained constant clinical status from the time of dropout
to the planned endpoint (Schalkwijk et al., 2014; Siddique
et  al., 2008). Other analytical methods have been pro-
posed to account for missing data, such as the mixed-effect
modeling of repeated measures, or defined outcomes have
been assessed even after subjects have dropped out of trials
(Schalkwijk et al., 2014; Siddique et al., 2008).
Finally, dropout rates of over 20% pose serious threats to
the validity of results obtained in trials (Schulz & Grimes,
2002). Regrettably, according to a recent systematic review,
this seems to be the case in approximately half of the bipo-
lar depression trials (Spanemberg et al., 2012).
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   611
L E V E L OF S IG N I F IC A NC E : P VA LU E
As stated earlier, high variability observed in bipolar
depression trials could lead to false-negative outcomes. On
the other hand, making repeated analysis of data greatly
augments the possibility of obtaining significant p values
(typically p < .05), that is, false positives. For example, the
chance of obtaining false positives (obtaining significance
by chance) for a p < .05 will be 5% when making one com-
parison, 10% for two comparisons, 23% for five compari-
sons, and so on (Ghaemi, 2009). This could be corrected
using different methods, such as the Bonferroni correction
or the Holm-Bonferroni correction, but the importance of
taking this into account is that, in order to avoid such kind
outcome measures for which the study should be adequately
powered.
On the other hand, in secondary analysis of infrequent
events (such as subgroup analysis or analysis on adverse
effects of a drug in a trial designed for efficacy outcomes), p
values may show false negative results, owing to diminished
statistical power by smaller groups (Ghaemi, 2009).
QUA L I T Y OF R E P ORT I NG
A recently published systematic review on quality of
reporting of RCTs on pharmacologic treatments of bipo-
lar disorders stated that “a good part of the reporting qual-
ity . . . falls well below the required standards and also the
practically feasible levels for many aspects, essential for
adequate interpretation of methodological quality and
clinical relevance” (Strech, Soltmann, Weikert, Bauer, &
Pfennig, 2011. p.  1220). The lack of standardisation in
RCTs reporting may influence their correct interpretation.
Besides, vital information in guiding clinical decisions and
for data pooling in the context of meta-analysis could be
missing (Undurraga & Baldessarini, 2012). Furthermore,
inadequate reporting and design have been associated with
biased treatment effect estimates (Moher et al., 2010). As a
result of this problem, the CONSORT statement was made
in the 1990s and has been revised periodically ever since
(Moher et al., 2010). It consists of a checklist of essential
items that should be included in reports of RCTs and a
diagram for documenting the flow of participants through
a trial, intended to provide guidance to researchers on
reporting of their RCTs. Importantly, many leading medi-
cal journals and major international editorial groups have
supported this initiative.
Strech et  al. (2011) systematically reviewed the lit-
erature to identify all RCTs involving pharmacologic
treatment of bipolar disorder published between 2000 and
2008. They included 105 RCTs and assessed their quality
of reporting based on the CONSORT statement (Moher
et al., 2010): 25% of trials reported inadequately and 42%
reported adequately. Reporting was especially poor for ran-
domization procedures: only 16% of trials defined the gen-
eration of the random allocation sequence and 15% defined
the method of allocation concealment. In addition, only
41% of trials reported on blinding measures for care pro-
viders and 46% for outcome assessors and only 2% reported
how the success of blinding was evaluated. In addition, only
32% reported on description of sample size calculations.
Furthermore, important variables such as education, dura-
tion of illness, and number of previous episodes were under-
reported (7%, 32%, and 42%, respectively). Finally, only 6%
of trials reported number needed to treat (NNT) and 15%
reported on the CI for the contrasts between groups.
When reporting outcomes, clinical applicability and
ease of interpretation are important goals. Effect size esti-
mations in general are easier to interpret and provide more
information than hypothesis testing (p values), though
they can be complementary. As reported previously, p value
considered alone is not helpful to guide clinical decisions,
as it can be clinically irrelevant and depend on design vari-
ables such as the sample size or on statistical analysis (e.g.,
repeated analysis leading to false positives). In addition,
total scores assessed by the symptom severity scales are dif-
ficult to interpret if the clinician is not familiar with them,
which is frequently the case. Alternative methods like sim-
ple effect size estimations such as Cohen’s d have been pro-
posed (Ghaemi, 2010; Martinez-Aran et al., 2008). Cohen’s
d is simply calculated as the difference between the study
arms for change in scores divided by their pooled standard
deviations. It is useful, as it corrects for the variation within
the sample and gives values between zero and 1 or higher. It
typically described as “small, 0.2,” “medium, 0.5,” or “large,
0.8” (Martinez-Aran et al., 2008). Other examples of effect
size estimations are SMDs, risk ratio, odds ratio, absolute
responder or remitter rates, NNT, and number needed to
harm (NNH), each being described in a preceding chapter
of this book. NNT and NNH are other clinically useful
effect estimates that inform clinicians about how many
patients one would need to treat with one intervention ver-
sus another to see a difference in an outcome (efficacy out-
comes, such as response, remission, etc. or adverse outcomes
such as tolerability, suicidal behaviors, etc.). In other words,
they can quantify the clinical relevance of a statistically sig-
nificant study result. Their main limitation is that they can
only be calculated for binary variables. Continuous vari-
ables should use other effect size measures (or be converted
61 2   •   S E C T I O N I V:   F U T U R E R E S E A R C H
to binary variables, e.g., yes/no response; Citrome, 2008).
Effect sizes should routinely be accompanied by their corre-
sponding CI or CrI, which is the estimate of precision. It is
“the range of plausible values for the effect size” or the “like-
lihood that the real value for the variable would be captured
in 95% of the trials” (Ghaemi, 2010). Of note, 95% CI is
equivalent to p value of .05 (but gives more information).
In conclusion, evidence on the efficacy and safety of
available treatments for bipolar depression is scarce and
highly heterogeneous. Many factors contributing toward
heterogeneity and statistical noise should be taken into
account when interpreting existing trials and designing
new clinical trials:  longer trial durations, higher number
of study arms, larger sample sizes, involvement of more
study sites, lower baseline disease severity, possibility of
doses adaptation, diversity of study populations and ethnic
factors, high dropout rates, less placebo washout of previ-
ous drugs, and low frequency of symptomatic assessments.
Moreover, bipolar disorder has complex clinical presenta-
tions that make establishing reliable and consistent diagno-
sis, clinical assessments, and (clinically relevant) outcome
definitions extremely important. Notably, in light of cur-
rent evidence, outcome assessments in bipolar depression
should also consider functional status.
Regarding assessment methods, the most frequently
used scales to assess depressive symptom severity and treat-
ment response (i.e., HDRS, MADRS, IDS) were initially
developed to evaluate unipolar major depressive disorder.
Newer depression scales developed specifically for bipolar
depression (e.g., BDRS) may be suitable for future trails of
bipolar depression. Indeed, the only way to overcome the
challenges posed by decreasing signal detection in depres-
sion RCTs may be the use of harder outcomes, such as spe-
cific biomarkers, which are yet to come (Vieta, 2014).
In addition, for statistical analysis of primary and sec-
ondary outcomes, a standard intention to treat approach
should be adapted as it offers a better model than the com-
pleter analysis but nevertheless is far from being unbiased.
It would be even better if new analytical methods such
as mixed-effect modelling of repeated measures could be
incorporated.
The last stage of research, reporting the results, is as
important as methodological planning and statistical
analysis. Regrettably, the reporting of results from bipolar
depression trials is generally of poor quality and associ-
ated with biased estimates of treatment effects. Guidelines
such as the CONSORT statement should be used as an aid
when reporting. Clinical applicability and ease of interpre-
tation, as well as possibility of future evidence synthesis,
should be considered. In that sense, change in scores and
their standard deviations for the entire sample, as well as
subgroups, should constantly be reported and may better
be accompanied by the standardized effect size estimations
such as SMD or Cohen’s d and responder and remitter rates,
as these measures are easier to interpret and provide more
information than hypothesis testing. NNT and NNH are
also clinically oriented and easy-to-interpret outcome mea-
sures that should be incorporated into reporting whenever
possible. Finally, as with bipolar mania trials, quantifiable
data on the special subgroups such as bipolar I or II, psy-
chotic versus nonpsychotic, with mixed features or rapid
cycling course, as well as individual adverse effects, should
be reported regularly with a standardized approach.
C L I N IC A L T R I A L S OF  cuted to enroll patients with acute, severe forms of bipolar
B I P OL A R M A I N T E N A NC E
(OR PROPH Y L A X I S) T R E AT M E N T
Standardized designs have been established for studies of
acute mania (and acute depression); however, no core design
for maintenance therapy for BD has been agreed on by
researchers in the field (Gitlin, Abulseoud, & Frye, 2010).
Therefore, it is uncertain whether the results reported
may be the product of differential efficacy between agents
or between different designs, thus creating inconsistent
results. Given the paucity of available maintenance trials
and the diversity of their designs due to the patient popu-
lations examined and pursued outcome (i.e., antimanic or
antidepressive prophylaxis as described by Grunze et  al.,
2013), more trials providing homogenous data on the mea-
sures of efficacy, as well as side effects, functionality, quality
of life, and prevention of suicide are needed. Such studies
will aid clinicians in providing more successful treatments
for bipolar prophylaxis.
E A R LY L I T H I U M T R I A L S
The early lithium trials have been heavily criticized due to
the discrepancies between their strikingly positive results
compared to those of subsequent comparative trials and
naturalistic data. In 1995 Moncrieff published an article
proposing that these discrepancies originate from the
design of these early studies (i.e., discontinuation studies
in which patients who had been receiving lithium were
allocated to either continue receiving lithium or to placebo
substitution; Moncrieff, 1995). Such studies fail to exam-
ine the efficacy of lithium prophylaxis in view of the sub-
stantial evidence that lithium withdrawal induces manic
relapse (Dunner, 1998; Schou, 1993). Irrefutably, special
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   613
care is imperative regarding the management of lithium
withdrawal (Mander & Loudon, 1988).
PL AC E B O - CON T ROL L E D
M A I N T E N A NC E T R I A L S
In 1997 Bowden et  al. reported data from the first
placebo-controlled maintenance trial in bipolar I disorder,
which has been conducted since 1973. Bipolar maintenance
trial methodologies have evolved substantially during this
time. Bowden et  al. argued that this particular study,
designed for submission to the regulatory agencies with
considerations on the country-specific requirements, have
had a strong influence on the study design. They also sug-
gest that maintenance studies should be designed and exe-
depression or bipolar mania, rather than recruiting patients
with remission or milder forms of BD. They suggested that
by paying greater attention to the frequency of manic and
depressive episodes and the severity of an index episode, the
statistical power of the study could be enhanced (Bowden
et al., 1997).
Unlike the acute treatment trials, with over 50 trials
for only acute bipolar mania being published, there is a sur-
prising paucity of maintenance studies. In a recent review
by Popovic, Reinares, Amann, Salamero, and Vieta (2011),
which included all the RCTs assessing the effectiveness
of drugs in the prophylactic treatment of BD compared
to placebo, only 15 trials satisfied the inclusion criteria
(Inclusion criteria were: a minimal duration of six months;
patients over 18; while exclusion criteria were: small
sample size (i.e., fewer than 17 subjects per arm); a study
sample not exclusively composed of bipolar patients; those
using rating scales not validated in patients with bipo-
lar disorder. Since then, further two trials satisfying the
same inclusion criteria have been published (Berwaerts,
Melkote, Nuamah, & Lim, 2012; Marcus et al., 2011). It
is noteworthy that some trials (e.g., McIntyre et al., 2010)
were excluded because they did not have a long-term pla-
cebo group. Some of the RCTs used a three-arm design.
Among the available 17 trials, there were 11 RCTs assess-
ing drugs in monotherapy and 6 for combined treatment
with mood stabilizers such as lithium and valproate. The
studies were not homogeneous with respect to clinical
characteristics of the sample (rapid-cycling course, manic/
mixed states or depression, refractory patients or unbi-
ased samples), sample size, and rates of study completion.
In that regard, as discussed by Popovic et al. (2012), most
studies enrolled enriched populations of patients who were
currently or recently manic or mixed. Missing from most
study designs was the recruitment of patients with index
depressive episodes. Exclusion of depressed patients at
enrollment may affect the polarity of mood episodes dur-
ing the blinded relapse prevention phase since the study
design was primarily configured to demonstrate efficacy in
the delay or prevention of manic recurrence.
The absence of depressive index episodes in a compound
whose primary spectrum of efficacy is in depression biases
outcome against the drug, or vice versa. However, the main
reason why some compounds have been studied only in
the context of index mania is their failure to separate from
placebo in acute bipolar depression trials; hence, the bias
against index depression is actually caused by the high
polarity index of the drug, indicating a stronger antidopa-
minergic action, which makes it more suitable for the treat-
ment of mania and the prevention of subsequent manic
episodes (Popovic et al., 2012).
The polarity index is a novel metric indicating the rela-
tive antimanic versus antidepressive preventive efficacy of
drugs, and it was retrieved by calculating NNT for preven-
tion of depression and NNT for prevention of mania ratio,
emerging from the results of the RCTs. The metric aims to
help clinicians to understand the prophylactic efficacy pro-
file of drugs used for the treatment of bipolar disorder by
translating results of clinical trials into real-world clinical
practice (Popovic et al., 2014). According to Vieta (2014),
in recent years we have started to measure the relative effi-
cacy of drugs for bipolar disorder by means of the NNT
(Popovic et  al., 2011)  and their profile according to the
polarity index (Popovic et al., 2012), which is a useful mea-
sure that can be easily misunderstood (Alphs, Berwaerts, &
Turkoz, 2013) since it actually provides advice on what not
to use, rather than what to use, depending on the predomi-
nant polarity of manic and depressive episodes in a given
patient (Baldessarini et al., 2012).
In fact, RCTs for maintenance treatment of bipolar
disorder are not only scarce; they are completely lack-
ing for various agents. Carbamazepine is a clear example;
although it was the first agent after lithium to be advocated
for long-term treatment of BD and two lithium-controlled
studies indicate the drug’s efficacy in relapse prevention,
no maintenance trials exist. As for valproate and oxcar-
bazepine, the only existing maintenance trials are nega-
tive/failed, thus further studies are clearly needed. Future
studies need to address the long-term effectiveness of
agents such as carbamazepine, oxcarbazepine, and valpro-
ate, as well as some antipsychotics, which have not been
assessed in long-term placebo-controlled studies. In fact,
successful long-term management often requires combina-
tion treatment. Lack of evidence base for this strategy (e.g.,
614   •   S E C T I O N I V:   F U T U R E R E S E A R C H
lamotrigine as add-on treatment) should also be an object
of future research.
DI S CON T I N UAT ION S T U DI E S
The methodological caveat of discontinuation studies is
that findings may demonstrate “discontinuation effects”
rather than preventing relapses. Additionally, because the
rate of relapse is low in these studies they require a very large
number of participants to reach adequate statistical power.
CON T I N UAT ION S T U DI E S
Continuation trials involve patients who have responded
to the relevant treatment in the acute phase and thus are
enriched for the possibility of relapse in the subsequent
continuation period. Since fewer participants are required,
maintenance trials switched to continuation studies.
The lack of consistency in the designs of the
placebo-controlled maintenance continuation studies
listed in Table 42.3 has weakened the reliability and valid-
ity of these studies. Therefore the available evidence for the
long-term treatment of bipolar disorder is lacking. More
rigorous approaches should involve analyses of bipolar
I and bipolar II subtypes or consideration of them in dif-
ferent trials as described in the studies outlined here. For
example, quetiapine has recently been indicated by the
FDA for monotherapy of bipolar I  and bipolar II depres-
sion. Although no specific controlled trial addressed the
efficacy and safety of quetiapine monotherapy in bipolar
II, BOLDER (BipOLar DEpRession) studies I and II, and
the EMBOLDEN continuation studies (described later)
included sufficient bipolar II patients (Parker, 2012).
The two EMBOLDEN studies constitute a good exam-
ple of the continuation of maintenance trials with an index
episode of bipolar depression. These two RCTs are similar
in design (i.e. multicenter, randomized, double-blind com-
parisons of the efficacy and safety of quetiapine monother-
apy [300 mg or 600 mg daily] verses placebo in bipolar I or
II disorder adults). The active comparator arm was lithium
in EMBOLDEN I and paroxetine in EMBOLDEN II. The
26- to 52-week continuation phase consisted of patients
who had achieved remission and were continued on the
same dose of quetiapine or were switched to placebo. In
their combined analysis, the authors demonstrated that
both doses of quetiapine significantly increased the time
to recurrence of any mood event. The subgroup analysis on
bipolar II disorder was available, and the risk of recurrence
of any mood event compared with placebo was significantly
reduced in this subpopulation of patients with bipolar II
Table 42 .3.  R ANDOMIZED CONTROLLED TR IALS ASSESSING THE EFFECTIVENESS OF DRUGS IN THE
PROPHYLACTIC TR EATMENT OF BIPOLAR DISOR DER COMPAR ED TO PLACEBO a

TR I AL (IN OR DER PATIENT INCLUSION DOSAGE (MG/DAY)

OF APPEAR ANCE CR ITER I A (M AINTENANCE DUR ATION NUMBER OR PLASM A LEVELS/MEAN
IN TEXT) PHASE) (W EEKS) R ANDOMIZED DOSAGE

Keck et al., 2007 Bipolar I 100 ARI = 78 ARI: 15–30mg/day

≥18 years PLA = 83 Mean: 23.8 mg/day
YMRS≤10
MADRS≤13
No hospitalization in previous
3 months
Tohen et al., 20063 Bipolar I 48 OLZ = 225 OLZ: 5–20 mg/day
≥18 years PLA = 136
YMRS≤12
HDRS≤ 8
2 prior mixed or manic episodes in
past 6 years

Tohen et al., 2004 Bipolar I 72 LI/VPA + PLA = 48 OLZ: 5–20 mg/day

18-70 years LI/VPA + OLZ = 51 Mean: 12.5 mg/day
YMRS≤12 LI: 0.66-0.86 mEq/l
HRSD-21≤ 8 VPA: 60.1–73.8 μg/mL

Vieta et al., 2008a Bipolar I 104 QUE + LI/VPA = 336 QUE: 400 -800 mg/day
≥18 years PLA + LI/VPA = 367 Mean: 497 mg/day
YMRS≤12 LI: 0.5–1.2 mEq/L
HDRS≤ 12 VPA:50–125 μg/mL

Suppes et al., 2009 Bipolar I 104 QUE + LI/VPA = 310 QUE: 400–800mg/day

≥18 years PLA + LI/VPA = 313 Mean: 519 mg/die
YMRS≤10 LI: 0.5–1.2 mEq/L
MADRS≤13 Mean: 0.71–0.74 mEq/L
VPA: 50–125 μg/mL
Mean: 68.91–71.38 μg/mL

Weisler et al. Bipolar I 104 QUE = 404 QUE: 300–800 mg/day

YMRS ≤12 LI = 364 Li: 0.6–1.2 mEq/L
MADRS ≤12 PLA = 404
Acute current or recent (past 26
weeks) manic, depressive, or mixed
index episode treated with QUE

Quiroz et al., 2010 Bipolar I 96 RLAI = 140 RIS: 12.5–50 mg i.m.

18–65 years PLA = 136 Mean:25mg
Recent manic/mixed episode or
stable patients with ≥1 mood epi-
sode in past 4 months

Macfadden et al., Bipolar I 52 RLAI + TAU = 65 RLAT: 25–50mg/2 weeks

2009 18–70 years PLA + TAU = 59
≥4 episodes in the past year

Bowden et al., 2010 Bipolar I 24 ZIP + LI/VPA = 127 ZIP: 80–160 mg/day

≥18 years PLA + LI/VPA = 113 LI: 0.6–1.2 mEq/L
Current or recent manic/mixed Mean: 0.7–0.9 mEq/L
episode VPA: 50–125 μg/mL
MRS≥14 Mean: 67.4–72.8

Bowden et al., 2003 Bipolar I 76 LAM: 59 LAM: 100–400mg/die

≥18 years LI: 46 LI: 0.8-1.1 mEq/L
Current or recent PLA:70
(hypo)mania
≥1 additional (hypo)manic and 1
depressive episode in the past 3 years

(continued)

S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   615
Table 42 .3  CONTINUED

TR I AL (IN OR DER PATIENT INCLUSION DOSAGE (MG/DAY)

OF APPEAR ANCE CR ITER I A (M AINTENANCE DUR ATION NUMBER OR PLASM A LEVELS/MEAN
IN TEXT) PHASE) (W EEKS) R ANDOMIZED DOSAGE

Calabrese et al., Bipolar I 72 LAM: 221 LAM:50-400mg/die

2003 ≥18 years LI: 121 Mean:200mg/die
Current or recent MDE PLA:121 LI: 0.8-1.1 mEq/L
≥1 additional (hypo)manic and 1 Mean: 0.8±0.3 mEq/L
depressive episode in the past 3 years

Calabrese et al., Bipolar I and II Rapid cycling 26 LAM: 90 LAM: 100–300 mg/day

2000 ≥18 years PLA: 87
≤14 HDRS
≤12 MRS
<3 on item 3 HDRS
stable for 4 weeks

Prien et al., 1973 Manic-depressive, manic type 24∗ LI:101 LI: 0.5-1.4 mEq/L
PLA: 104

Bowden et al., Bipolar I 52 VPA: 187 VPA: 71-125 μg/mL

2000 18-70 years LI: 90 LI: 0.8-1.2 mmol/L
Manic episode ≤3 months before PLA:92
randomization.
MRS ≤11
DSS ≤13
GAS >60,
No serious suicidal risk

Vieta et al., 2008b Bipolar I or II 52 OXC + LI=26 OXC: 1200 mg/day

≥18 years PLA + LI=29 LI:0.6 mEq/l
YMRS≤12
MADRS≤20
No acute phases in 6 months

Marcus et al., 2011 Bipolar I 52 ARI + LI/VPA=168 ARI: 15-30mg/day

YMRS ≥16 PLA + LI/VPA=169
Current or recent manic/mixed
episode
Inadequate response to lithium
or valproate YMRS ≥16 and ≤35%
decrease from baseline at 2 weeks

Berwaerts, 2012 Bipolar I Until the patients PALI=152 PALI: 3- 12 mg/day

18 -65 years experienced PLA=148 OLZ: 5-20 mg/day
Current manic or mixed episodes recurrence OLZ=83
At least 2 previous
mood episodes (1 of which had to
be a manic or mixed episode) within
3 years before
screening
YMRS ≥20 at
baseline.
No significant
risk for suicidal or violent behavior;
no borderline or
antisocial personality disorder

NOTE: Adapted from: Popovic et al. (2011).

a
With a minimal duration of 6 months and in patients aged over 18.
with both doses of quetiapine (McElroy et al., 2010; Young
et  al., 2010). The strengths of these two EMBOLDEN
studies are (a) the large patient population (n =1542 (565
bipolar II)) and (b) the continued treatment of responsive
patients with quetiapine or placebo (using a randomized
withdrawal design). Thus the authors were able to inves-
tigate the maintenance of effect associated with ongoing
quetiapine treatment. Additionally, subgroup analyses for
the bipolar subtypes were included and the study involved
the largest bipolar II patient population studied to date in a
continuation treatment study (McElroy et al., 2010).
OU TCOM E S A S S E S SM E N T S A N D
R ECOM M E N DAT IONS FOR F U T U R E
M A I N T E NA NC E T R I A L S
The primary outcome measures in bipolar disorder main-
tenance trials vary greatly, making the comparison of effi-
cacy of medication across studies difficult (Grunze et  al.,
2013). The majority of long-term studies use the results of
Kaplan–Meier (KM) survival analyses based on time to
intervention as the primary outcome. Other studies have
used “any reason of failure” (i.e., new mood episodes, need
for additional treatments, hospitalization, adverse events,
withdrawal of consent, lost to follow-up) as primary out-
comes. Some previous studies have used dropout for emerg-
ing new episodes (using Diagnostic and Statistical Manual
of Mental Disorders [fourth edition] criteria/clinical rating
scale thresholds). The problem with KM survival analytic
techniques are that they measure the occurrence of a pre-
defined event, for example, treatment emergent episode
intervention, discontinuation, at baseline (absence of the
event) and endpoint (occurrence of event) only (Grunze
et al., 2013). Grunze et al. state that KM survival analytic
techniques are not entirely appropriate considering that
“completely healthy” between-episode states are unlikely
given the subsyndromal fluctuations of mood, impaired
functioning, and quality of life associated with bipolar dis-
order and also due to the failure to capture tolerability and
impact on health data. Grunze et al. suggest that the reason
for the popularity of the KM techniques is they are more
sensitive to measuring differences than the more traditional
counting of failures. Instead of KM analyses, some studies
have used mean change over time of symptomatic rating
scales such as the YMRS and MADRS (McIntyre, 2010;
Tohen et al., 2003). The limitation of the change over time
analyses is that only minor shifts of statistical means for all
patients are captured using this method.
As indicated in Chapter 43 of this book, one option for
assessing daily or weekly subsyndromal mood fluctuations
S trategies for I mprov ing R andomized T rial E v idence for T reatment of B ipolar D isorder   •   617
versus full clinical relapse (in addition to repeated use of
cross-sectional scales) is the National Institute of Mental
Health Life Chart Method™ (NIMH-LCM™), which has
both a clinician-rated and a self-rated version for assessing
severity of mania and depression on a daily basis (Post &
Yildiz, 2014). This scale can also track extremes of cycling,
presence of dysphoric mania, and comorbid symptoms. In
addition, it has a running tally of medications and a space
for rating side effects with mild, moderate, or severe impact.
Reliability is excellent, as severity of mania and depression
is rated on the degree of functional impairment with which
each phase is associated, making recall of severity relatively
easy even at intervals of several weeks to a month between
rating sessions. The scale has been validated against other
measures and used productively in a number of studies,
including long-term comparisons of lithium versus carbam-
azepine versus the combination for one year of prophylaxis
for each phase; comparisons of lamotrigine, gabapen-
tin, and placebo; and, most recently, detailed analyses of
lamotrigine’s long-term effects on mood stability (Post &
Yildiz, 2014). Related longitudinal ratings that have been
employed by the STEP-BD program are also endorsed, as
such detailed description of the precise course of illness
is particularly important in instances of extreme rapidity
of cycling, which can even occur in bipolar outpatients in
demanding professions.
One of the major assets of such detailed longitudi-
nal ratings is the ability to simultaneously assess different
thresholds for what one might consider as mild, moderate,
or severe relapse, as well as employ modal measures such as
that of area under the curve, signifying the magnitude and
duration of mania and depression. Such a measure of area
under the curve allows for precise intraindividual compari-
sons of the degree of symptomatology observed prior to and
after a given experimental manipulation as a continuous
variable, which should vastly increase the power to detect
treatment difference compared with a single endpoint of
percentage of relapse into a new episode.
Traditional designs in assessment of the efficacy of a
prophylactic treatment have typically required patients to
achieve substantial improvement or remission for a given
period of time, then are randomized and followed up until
the occurrence of a new episode or need for clinical inter-
vention. While this has merits inpatient populations in
whom this degree of wellness is readily achieved, it is far
from ideal for those with highly treatment-resistant illness.
In order to enable future pooled analyses of bipo-
lar maintenance trials’ results, besides a standardized
approach on the efficacy measures in terms of prophylaxis
from emerging manic or depressive episodes, future RCTs
should also quantify data on the important side effects such
as weight gain or metabolic syndrome, undesirable neuro-
logical or cognitive effects, and TEAS, as well as quality of
life, total life years gained, and functionality, in a standard-
ized approach.
Given that BD is an especially heterogeneous condi-
tion, it might be wise to allow a limited degree of “pre-
planned diversity” into the maintenance trials, provided
that equal allocation into study arms is maintained,
objective outcome assessments are utilized, and, most
important, similarity and transitivity of the trials are not
jeopardized. More RCTs and more secondary outcomes
in wisely planned designs may enable more effective clini-
cal decision-making by utilizing advanced meta-analyses
methods involving direct and indirect comparisons, sen-
sitivity analysis, and meta-regressions. In order to achieve
this we suggest (a) employment of the NIMH-LCM™ for
detection of daily or weekly subsyndromal mood fluc-
tuations in addition to weekly or biweekly assessments of
mania and depression cross-sectionally via employment of
standardized scales such as the YMRS and MADRS as
appropriate; (b)  employment of 52 weeks of study dura-
tion; (c)  study designs that avoid withdrawal or discon-
tinuation effects; (d) regular and standardized assessment
and reporting of all important side effects such as weight
gain or metabolic syndrome, undesirable neurological or
cognitive effects, and TEAS, as well as quality of life, life
years gained, and functionality; (e)  regular reporting on
the lifetime occurrence of depressive versus manic/mixed
episodes and subgroup analysis on patients with predomi-
nantly depressive versus manic/mixed polarity; (f) regular
reporting on the lifetime occurrence of psychotic features
and subgroup analysis on patients with psychotic versus
nonpsychotic features; and (g)  regular reporting on the
occurrence of rapid cycling features and subgroup analy-
sis on patients with rapid cycling versus nonrapid cycling
features.
Disclosure statement:  Dr.  Ayşegül Yildiz has received
research grants from or served as a consultant to, or
speaker for, Abdi Ibrahim, Actavis, AliRaif, AstraZeneca,
Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Pfizer,
Sanofi-Aventis, and Servier.
Dr.  Eduard Vieta has received grants and served as
consultant, advisor or CME speaker for the following
entities:  AstraZeneca, Bristol-Myers Squibb, Elan, Eli
Lilly, Ferrer, Forest Research Institute, Gedeon Richter,
Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Johnson &
Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer,
Roche, Rovi, Sanofi-Aventis, Servier, Shire, Solvay,
618   •   S E C T I O N I V:   F U T U R E R E S E A R C H
Sunovion, Takeda, Teva, the Spanish Ministry of Science
and Innovation (CIBERSAM), the Seventh European
Framework Programme (ENBREC), and the Stanley
Medical Research Institute.
Dr.  Dina Popovic’s work is supported by a Sara
Borrell post-doctoral grant, provided by Carlos III
Institute (CD13/00149), Spanish Ministry of Science and
Innovation. Dr. Popovic has received research grants from,
or served as a speaker for, Bristol-Myers Squibb, Merck
Sharp & Dohme, and Janssen-Cilag.
Dr. Sarah Wooderson is employed by King’s College
London. This chapter presents independent research part-
funded by the National Institute for Health Research
(NIHR) Biomedical Research Centre at South London
and Maudsley NHS Foundation Trust and King’s College
London. The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the
Department of Health. No external funding was used for
this study.
Dr.  Allan Young is employed by King’s College
London; Honorary Consultant SLaM. He has given paid
lectures and been on advisory boards for all major phar-
maceutical companies with drugs used in affective and
related disorders. He has no share holdings in pharmaceu-
tical companies. He was lead investigator for Embolden
Study (AZ), BCI Neuroplasticity Study, and Aripiprazole
Mania Study and has participated in investigator-initiated
studies from AZ, Eli Lilly, Lundbeck, and Wyeth. Grant
funding (past and present) includes:  USA:  National
Institute of Mental Health, Brain and Behavior Research
Foundation (NARSAD), Stanley Medical Research
Institute; Canada: Canadian Institutes of Health Research,
UBC-VGH Foundation, WEDC, CCS Depression
Research Fund, MSFHR; UK:  MRC; Wellcome Trust;
Royal College of Physicians; BMA; NIHR. 
This chapter presents independent research part-
funded by the National Institute for Health Research
(NIHR) Biomedical Research Centre at South London
and Maudsley NHS Foundation Trust and King’s College
London. The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the
Department of Health.
Dr. Juan Undurraga has not disclosed any conflicts of
interest.
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