International Journal of Neuropsychopharmacology (2019) 22(8): 467–477

doi:10.1093/ijnp/pyz018
Advance Access Publication: April 19, 2019
Review

Review
Improving Functioning, Quality of Life, and

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Well-being in Patients With Bipolar Disorder
Caterina del Mar Bonnín, María Reinares, Anabel Martínez-Arán,
Esther Jiménez, Jose Sánchez-Moreno, Brisa Solé, Laura Montejo,
Eduard Vieta
Bipolar and Depressive Disorders Unit, Institute of Neurosciences, Hospital Clinic, University of Barcelona,
IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
Correspondence: Anabel Martínez-Arán, PhD, Clinical Institute of Neuroscience. Hospital Clinic of Barcelona, Villarroel, 170. 08036 Barcelona, Catalonia
([email protected]).

Abstract
People with bipolar disorder frequently experience persistent residual symptoms, problems in psychosocial functioning,
cognitive impairment, and poor quality of life. In the last decade, the treatment target in clinical and research settings has
focused not only on clinical remission, but also on functional recovery and, more lately, in personal recovery, taking into
account patients’ well-being and quality of life. Hence, the trend in psychiatry and psychology is to treat bipolar disorder in
an integrative and holistic manner. This literature review offers an overview regarding psychosocial functioning in bipolar
disorder. First, a brief summary is provided regarding the definition of psychosocial functioning and the tools to measure it.
Then, the most reported variables influencing the functional outcome in patients with bipolar disorder are listed. Thereafter,
we include a section discussing therapies with proven efficacy at enhancing functional outcomes. Other possible therapies
that could be useful to prevent functional decline and improve functioning are presented in another section. Finally, in the
last part of this review, different interventions directed to improve patients’ well-being, quality of life, and personal recovery
are briefly described.

Keywords:  bipolar disorder, psychotherapy, functional outcome, quality of life

Introduction
Bipolar disorder (BD) is a recurrent and chronic disorder char- also return to normal functioning and attainment of a mean-
acterized by fluctuations in mood state and energy that af- ingful life. In fact, in 1988, Dion and colleagues already pointed
fects around 2.4% of the global population (Merikangas et al., out that factors other than symptoms were related to func-
2011). As a lifelong and recurrent illness, BD is associated with tioning of patients with BD and that treatment should target
functional decline, cognitive impairment, and a reduction in symptom amelioration as well as reduce a patient’s disability
quality of life (QoL) (Martínez-Arán et al., 2004; Michalak et al., (Dion et al., 1988). It is known that even after the first manic
2005; Bonnín et al., 2012). Given the complexity of this illness episode, only 1 out of 3 patients regains psychosocial func-
and its consequences, researchers and clinicians are not only tioning at 1 year follow-up (Tohen et al., 2000), suggesting that
focused on clinical remission but also functional recovery functional outcomes in BD are undoubtedly impaired from the
and, more lately, well-being too (Vieta and Torrent, 2016). This very beginning and should become a priority in therapeutic
emergent paradigm includes not only symptom recovery but interventions.

Received: February 13, 2019; Revised: April 9, 2019; Accepted: April 16, 2019
© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 467
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468 | International Journal of Neuropsychopharmacology, 2019

In the last decade, many efforts have been made to improve functioning and disability irrespective of diagnosis; that is, it can
functioning and well-being in BD; hence, this review aims at pro- reflect difficulties due to any medical or psychiatric illness. In
viding a brief overview of both issues. First, the definition and contrast, both the GAF and the FAST are limited to the impact of
how to measure functioning is discussed. Then, a brief review the psychiatric disease on functioning, excluding the medical or
of the variables influencing psychosocial functioning is per- environmental limitations. The GAF, FAST, WHODAS 2.0, or ICF
formed. The following sections present some treatments that core sets specific for BD (Vieta et al., 2007; Ayuso-Mateos et al.,
have proven to be effective at enhancing functional outcomes 2013) are clinical tools, either rater administered (GAF, FAST,
and other promising treatments that might also be useful at ICF core sets) or self-administered (WHODAS 2.0), but other ap-
targeting functional impairment and prevent functional de- proaches exist. For instance, the UCSD Performance-based skills
cline. Finally, a brief overview of therapies directed to improve Assessment (UPSA) (Patterson et al., 2001) is based on task per-
well-being and QoL is also presented. formance and measures functional capacity, assessing the skills
involved in community tasks such as comprehension and plan-
ning, finance, communication, mobility, and house manage-
Definition of Psychosocial Functioning and

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ment. Figure 1 represents an overview of some different scales
How to Measure It available to measure functioning in BD during the last 40 years,
Despite the importance of psychosocial functioning in BD there starting in 1980, when the GAF was first endorsed by the DSM-III
is not a clear consensus regarding its definition. In the Task until the present.
Force for the International Society for Bipolar Disorders con- The scales presented in Figure 1 are just a little part of the big
ducted by Tohen and colleagues in 2009, different definitions of picture of the measurement of psychosocial functioning in BD.
psychosocial functioning were examined but without reaching Nevertheless, it fairly represents the great variability that exists.
a consensus. The experts highlighted the definition provided It is likely that the way the researcher or clinician defines psy-
by the International Classification of Functioning, Disability chosocial functioning will determine the tool to measure it, but
and Health (ICF) in which functioning comprises 3 different the reverse is true as well: the use of one tool or another implies
components: body structures and functions; activities and par- how the concept of psychosocial functioning is understood. To
ticipation; and personal environmental factors. Moreover, the overcome this bias, it would be ideal that psychosocial func-
authors of these guidelines underlined that this construct was tioning could be measured taking into account 3 different per-
complex to measure and that besides the ICF, the Functioning spectives: (1) a subjective view using a self-administered scale,
Assessment Short Thest (FAST) scale (Rosa et  al., 2007) might such as the Sheehan Disability Scale for BD (SDS) (Arbuckle
also constitute a good approach to measure functioning (Tohen et al., 2009) or the WHODAS 2.0; (2) a semi-objective scale, using
et al., 2009). Before these guidelines, there were other attempts the FAST, GAF, or LIFE-RIFT (Leon et al., 1999), which are inter-
to define psychosocial functioning. For instance, in 2000, Zarate viewer rated based on patients’ answers; and finally (3) an ob-
and colleagues suggested the assessment of psychosocial func- jective scale, like the UPSA, which is performance based and
tioning should involve different behavioral domains such as the measures functional capacity. Combining these 3 different ap-
individuals’ ability to function socially or occupationally, to live proaches might help to disentangle all the variables associated
independently, and to engage in a romantic life, with functional with functional impairment observed in BD.
recovery typically being defined as the restoration of normal
role functioning in the domains under scrutiny (Zarate et  al., Variables Influencing Functional Outcome
2000). This definition represented a breakthrough in the field be-
in BD
cause in that moment, psychosocial functioning was measured
by means of the Global Assessment Functioning Scale (GAF), Many variables have been associated with functional outcome in
endorsed by several consecutive editions of the Diagnostic and BD, including demographic, clinical, and neurocognitive factors.
Statistical Manual of Mental Disorders (DSM). The GAF pro- The brief summary presented below includes findings reported
vides 1 single score without differentiating between the behav- in some studies that use different scales, including the GAF,
ioral domains pointed by Zarate and colleagues. Despite all, the FAST, The Multidimensional Scale of Independent Functioning
GAF is still the most commonly used clinician rating scale to (Berns et al., 2007), and SDS among others. As mentioned above,
measure disability, at least in the United States (Von Korff et al., there is a great variability not only in the assessment of func-
2011). In 2007, Rosa and colleagues developed a tool to measure tioning but also in the variables reported to influencing it.
functioning, the already mentioned FAST scale. It was specific- Despite this, the next paragraphs are useful to reveal the mag-
ally created to measure the most common difficulties experi- nitude of the complex construct that researchers and clinicians
enced by patients with BD. The rationale behind this scale is in are trying to predict.
line with the definition of functioning proposed by Zarate and Concerning the sociodemographic factors, it seems that
colleagues in 2000, mostly focused on the assessment of dif- male patients (Tohen et al., 1990; Sanchez-Moreno et al., 2018) as
ferent behavioral domains. More specifically, the FAST targets well as older patients (Sanchez-Moreno et al., 2018) show poorer
the following areas: autonomy, occupational functioning, cog- functional outcomes. On the other hand, being married could
nitive functioning, financial issues, interpersonal functioning, represent a protective factor against functional impairment
and leisure time. In this regard, the FAST represented several (Kupfer et  al., 2002; Wingo et  al., 2010). Higher socioeconomic
advantages over the GAF, mainly that it assesses different be- status, based on education and employment, has also been
havioral domains, it does not rate the symptomatology, and it associated with better functional outcomes (Keck et  al., 1998;
is specific for BD. Wingo et al., 2010).
Currently, the DSM-5 no longer encourages the use of the Regarding the clinical variables, the presence of subsyndromal
GAF. Instead, the use of the World Health Organization Disability depressive symptoms has been consistently reported as
Assessment Schedule 2.0 (WHODAS 2.0) (Üstün et  al., 2010) is the strongest factor associated with functional impairment
recommended. The WHODAS 2.0 allows the assessment of (Tohen et  al., 1990; Bonnín et  al., 2010, 2012; Gitlin et  al., 2011;
Bonnín et al.  |  469

1980 2000 2001 2007 2009 2013 Present

UPSA
DSM-III starts (Paerson
endorsing GAF et al., 2001) DSM-5 starts
FAST scale endorsing
(Rosa et al., 2007) WHODAS 2.0
LIFE-RIFT A measurement of funconing
ICF core sets and do not
(to assess combining three perspecves is

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for BD (Vieta et recommend the
funconing in recommended:
al., 2007) use of the GAF
affecve 1) a subjecve assessment (using a
Validaon of anymore.
disorders) (Leon self-administered scale);
et al., 2000)
the MSIF for
2) a semi-objecve assessment
BD (Berns et al., Validaon of
2007) (using interviewer-rated scales)
the SDS for BD 3) an objecve assessment using
(Arbuckle et al.,
2009)
performance-based tools.

Figure 1.  Timeline representing some scales to measure psychosocial functioning in bipolar disorder over the last 40 years. FAST, Functioning Assessment Short Test;
GAF, Global Assessment of Functioning Scale; ICF, International Classification of Functioning, Disability, and Health; LIFE-RIFT, The Range of Impaired Functioning Tool;
SDS, Sheehan Disability Scale; MSIF, Multidimensional Scale of Independent Functioning; UPSA, the UCSD Performance-based skills Assessment; WHODAS 2.0, World
Health Organization Disability Assessment Schedule.

Gutiérrez-Rojas et  al., 2011; Reinares et  al., 2013; Samalin et  al., previously mentioned, the link between functional outcomes
2016; Murru et al., 2018). Other clinical variables include history of and neurocognition is well recognized, which is why in recent
psychosis, episode density, poor sleep quality, and longer illness years many efforts have improved cognition, including both
duration (Huxley and Baldessarini, 2007; Sanchez-Moreno et al., pharmacological and psychological treatments. In fact, new
2009a, 2010; Reinares et al., 2013; Etain et al., 2017; Murru et al., trends in pharmacological treatments include focusing on re-
2018). Psychiatric comorbidity, particularly with substance use storing cognitive functioning rather than psychosocial func-
disorder (e.g., cannabis, alcohol) and personality disorders, can tioning. Among the most promising medical treatments to
also negatively influence functional outcomes in patients with improve cognition in BD are mifepristone (Watson et al., 2012),
BD (Sánchez-Moreno et  al., 2009b; Leen et  al., 2013; Icick et  al., lurasidone (Yatham et al., 2017), and erythropoietin (Miskowiak
2017; Kizilkurt et al., 2018; Williams and Simms, 2018). et  al., 2014, 2015). Given the link between neurocognition and
Finally, regarding neurocognitive variables, verbal memory psychosocial functioning, it is likely that the efforts directed to
has been found to be a good predictor of functional outcome in improve neurocognition will also improve functional outcome;
several studies (Martinez-Aran et  al., 2007; Bonnín et  al., 2010, however, so far, no studies on pharmacological treatments have
2014, Torres et  al., 2011; Jiménez-López et  al., 2018), However, addressed both issues at the same time. It is worth mentioning
variables related to other neurocognitive areas have also been that the methodological recommendations for cognition trials
reported, including executive functions, processing speed, and by the Cognition Task Force from the International Society
attention (Jaeger et al., 2007; Mur et al., 2009; Wingo et al., 2010). for Bipolar Disorders encourage the inclusion of a functional
It might be hypothesized that the neurocognitive variables measure as a key secondary outcome (Miskowiak et  al., 2017).
influencing functional outcome in BD may vary depending on In this regard, a tool to measure functional improvement that
illness progression. For instance, patients in early stages of the allows the researchers and clinicians to classify patients into
disease seem to present a more selective profile of cognitive im- different categories of functional performance could be useful
pairment, with some domains capable of improving 1 year after to assess the efficacy of these treatments (Bonnín et al., 2018a).
the first manic episode, including improvements in processing
speed and executive functions (Torres et al., 2014). In this line, Psychological Therapies
at least 2 studies have found that first-episode patients who
In contrast to the area of pharmacological treatments, in the
did not relapse during 1-year follow-up could improve their
field of psychological interventions several efforts have been
neurocognitive functioning (Kozicky et al., 2014; Demmo et al.,
made lately to design therapies to restore psychosocial func-
2018); hence, preserving neurocognition from the very begin-
tioning in BD. The first attempt was an open trial using a pro-
ning of the illness might guarantee better functional outcomes.
gram named Cognitive Rehabilitation (Deckersbach et al., 2010).
The authors included a total of 18 patients with subsyndromal
Restoring Psychosocial Functioning: depressive symptoms and after 14 session of cognitive rehabili-
Therapies That Have Improved Functional tation, patients improved cognitive performance and functional
outcome. More interestingly, the findings showed that changes
Outcome
in executive function accounted, in part, for the improvements
in occupational functioning. The first randomized controlled
Pharmacological Interventions
trial (RCT) implementing a similar therapy was conducted in
Research on pharmacological and nonpharmacological treat- 2013 by Torrent and colleagues (Torrent et  al., 2013). The ef-
ments to restore functioning in BD is still immature. As ficacy of functional remediation (FR) was proved in terms of
470 | International Journal of Neuropsychopharmacology, 2019

improving functional outcomes in euthymic patients with mod- not be linear and unidirectional; instead, they seem to influ-
erate to severe functional impairment at baseline. Moreover, ence one another (Gitlin and Miklowitz, 2017; Weinstock and
improvement in psychosocial functioning was maintained after Miller, 2008). Besides the implications in functional outcome,
6 months’ follow-up (Bonnin et al., 2016). However, the impact residual depressive symptoms are also a major cause of relapse
of the intervention was low in terms of cognition. Contrary to (Vieta and Garriga, 2016; Radua et  al., 2017), consequently af-
others therapies labeled as “cognitive remediation,” FR is spe- fecting psychosocial functioning and QoL (Bonnín et  al., 2012;
cially centered on functional recovery, focusing on the training Xiang et al., 2014). The treatment of residual depressive symp-
of neurocognitive skills that are useful for daily functioning. toms during euthymia is an unmet need, but fortunately, clin-
Hence, this approach might be suitable especially for patients ical research has begun to investigate how to tackle them. One
in late stages of the illness and who present moderate to severe recent RCT proved that adjunctive extended-release quetiapine
functional impairment. Another preliminary study conducted at a dose of 300 mg daily was significantly more effective than
in the Netherlands included 12 patients and replicated the placebo in the treatment of subthreshold depressive symptoms
positive results in functional outcome after receiving a shorter (Garriga et  al., 2017), but no significant improvement was de-

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FR program (Zyto et  al., 2016). However, not all the interven- tected in functional outcome. One possible explanation is that
tions targeting cognitive rehabilitation were found to improve the sample size was not powered enough to detect significant
functional outcome. For instance, another RCT conducted by changes in this secondary outcome.
Demant and colleagues (2015) found no improvement on either Regarding psychological interventions, a limited number
cognition or functional outcome after a 12-week interven- of therapies have addressed subthreshold depressive symp-
tion. It is worth mentioning that these negative results might toms as a primary outcome. To the best of our knowledge,
be explained by some methodological limitations of the trial, only one pilot RCT study assessed the effect of Eye Movement
including the length of the intervention (too short) or the fact Desensitization and Reprocessing therapy on this type of symp-
that patients were subsyndromic at study enrolment. Another tomatology. Specifically, patients in the treatment group showed
study leaded by Lewandowski and colleagues (2017) assessed a statistically significant improvement in depressive and hypo-
the efficacy of an internet-based cognitive remediation program manic symptoms when compared with treatment as usual at
in patients with BD compared with an active control group both 12-month follow-up; however, psychosocial functioning was
in neurocognition and community functioning. After treatment, not assessed (Novo et  al., 2014). Another multicenter study of
patients who received the internet-based program improved Eye Movement Desensitization and Reprocessing with a bigger
cognitive performance in processing speed, visual learning sample is underway with the objective to reduce symptoms
and memory domains, and the composite score. These results and relapses and improve psychosocial functioning (Moreno-
were maintained over 6  months after finishing the interven- Alcázar et al., 2017). Regarding FR, secondary analyses showed
tion; however, the intervention was not associated with change that patients with subsyndromal symptoms could also improve
in community functioning, although cognitive change was as- psychosocial functioning after the therapy (Sanchez-Moreno
sociated with functional change across the sample. There are et al., 2017).
other ongoing trials targeting cognition including action-based Other therapies include an approach testing the long-term
cognitive remediation programs in which computerized training efficacy of an intervention that combined cognitive behavior
is combined with practical in-session activities and cognitively therapy (CBT) and psychoeducation, which has also been
challenging tasks between sessions. This novel approach may described to be effective in terms of symptoms and social-
have greater effect at enhancing functional outcomes than trad- occupational functioning improvement (González-Isasi et  al.,
itional cognitive remediation programs (Bowie et  al., 2017; Ott 2014). Positive results in social functioning were also found with
et al., 2018). CBT (Lam et al., 2003). Inder and colleagues (2015) randomized
It is difficult to measure the power of these current ap- a group of patients with BD to Interpersonal and Social Rhythm
proaches in changing functioning, since very few studies have Therapy or specialist supportive care, and both groups improved
used psychosocial functioning as a primary outcome. In this re- in depressive/manic symptoms and social functioning. Finally,
gard, meta-analyses providing these data are urgently needed. an intensive psychotherapy (family-focused treatment [FFT],
Interpersonal and Social Rhythm Therapy, or CBT) in patients
with BD during an acute depressive episode also showed bene-
How to Prevent Functional Decline:
ficial functional outcomes (Miklowitz et al., 2007a). Finally, posi-
Promising Therapies tive results have also been reported on anxious and depressive
So far, there is no strong evidence regarding the prevention of symptoms using mindfulness-based cognitive therapy (Williams
functional decline in BD. The following section includes some et al., 2008; Ives-Delipery et al., 2013; Perich et al., 2013).
targets and treatments that could address this issue and de- Although more research is needed, it might be hypothesized
serve to be further explored. that treating subthreshold depressive symptoms could be an in-
direct pathway to improve psychosocial functioning.

Addressing Subthreshold Depressive Symptoms

Enhancing Cognitive Reserve
A considerable portion of the patients with BD (more than 50%)
experience inter-episode residual depressive symptoms (De Cognitive reserve (CR) is the capacity of the adult brain to en-
Dios et al., 2010; Gitlin et al., 1995), preventing them from living dure neuropathology, minimizing clinical manifestations and
to the fullest. In this regard, subthreshold depressive symptoms allowing a successful accomplishment of cognitive tasks (Stern,
together with neurocognitive impairment might be one of the 2009). Genetics determine, to some extent, CR; however, environ-
strongest predictors of functional outcome (Bonnín et al., 2010, mental factors such as an active lifestyle, education, and brain
2012, 2014; Reinares et al., 2013; Martinez-Aran and Vieta, 2015; stimulation (mental activities) can also influence it. In BD the
Samalin et  al., 2017). However, the relationship between func- most common ways to measure CR include years of education,
tional outcome and subthreshold depressive symptoms might premorbid Intelligence Quotient, and leisure activities. So far,
Bonnín et al.  |  471

no interventions have tested whether improving CR enhances exercise-induced BDNF upregulation (Nuechterlein et al., 2016;
functioning, but some studies suggest that CR is a good pre- Campos et al., 2017).
dictor of both cognitive and psychosocial outcome in euthymic
patients with BD (Anaya et al., 2012; Forcada et al., 2015). Further, Multicomponent Programs
it could also play an important role in patients with first psych-
otic episode since CR has shown to predict psychosocial func- One advantage of this type of intervention is to tackle different
tioning 2  years after the first episode (Amoretti et  al., 2016). areas to be improved at the same time, hence, allowing a holistic
Hence, given the role of CR both in chronic patients and at early treatment of patients, taking into account not only education on
stages, this might constitute an area to explore and enhance to the illness but also how to improve healthy lifestyles and func-
prevent functional decline (Vieta, 2015). In this regard, there is tional outcomes. Following the premise that no single psychosocial
another ongoing trial by Torrent and colleagues (NCT03722082) intervention might be sufficient to address the morbidity, the func-
that aims to enhance CR in child, adolescent, and young adult tional impairment and the consequences associated with severe
offspring of patients diagnosed with schizophrenia or BD; how- mental illnesses (Kern et al., 2009), multicomponent programs, and

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ever, so far, no preliminary results are available.  care packages are being developed for patients with BD.
An example of this kind of treatment that has proven to be
effective in BD is the Integrated Risk Reduction Intervention de-
Diet and Physical Exercise
veloped by Frank and colleagues (2015). More specifically, this
Nutrition and physical exercise play a critical role in both the program consists of 17 sessions grouped in different modules,
mental and physical health of patients with BD. Physical in- including psychoeducation, training to improve sleep/wake
activity and poor diet habits can contribute to obesity, diabetes, patterns and social rhythm regularity, nutrition, physical ac-
hypertension, and dyslipidemia, which, in turn, increase the risk tivity, and healthy habits (smoking cessation). Results from this
for cardiovascular disease (Soreca et al., 2008). At any rate, these study showed that patients who followed the intervention sig-
risk factors should be targeted since it has been shown that nificantly reduce their BMI. Moreover, 3 variables (C-reactive
obesity can also impact cognitive functioning (Mora et al., 2017), protein, total cholesterol, and instability of total sleep time) con-
and in turn, cognitive impairment could be a predictor of weight tributed to a combined moderator of faster decrease in BMI with
gain (Bond et  al., 2017). Hence, it seems that weight increase Integrated Risk Reduction Intervention treatment.
and cognitive impairment can influence one another. Moreover, Recently, the Bipolar Disorder and Depression Unit in Barcelona
another study has found that increased body mass index (BMI) has developed an integrative approach consisting of therapeutic
was associated with a more chronic course of the disease, longer components of broader programs that the Barcelona Bipolar
duration of illness, and lower psychosocial functioning (Calkin Disorders Program had previously developed and whose effect-
et al., 2009). In line with this, Bond and colleagues (2010) found iveness had been proven separately, such as psychoeducation for
that those patients who suffered a clinically significant weight patients (Colom et  al., 2003), psychoeducation for family mem-
gain (defined as gaining ≥7% of baseline weight over 12 months) bers (Reinares et al., 2008), and FR (Torrent et al., 2013). In addition,
had significantly poorer functional outcomes at 12-month an important emphasis is given to the promotion of a healthy
follow-up, and, interestingly, functional impairment was inde- lifestyle, and a module focused on mindfulness-based cogni-
pendent from current mood symptoms. tive therapy has also been included. Therefore, some contents of
Poor dietary habits and a sedentary lifestyle can increase psychoeducation for patients have been combined with a session
physical and psychiatric morbidity, worsen psychosocial and for family members and complemented with aspects related to
cognitive functioning, and predict a poor pharmacological re- health promotion, mindfulness training, and strategies for cog-
sponse. That is why clinicians treating individuals with BD face nitive and functional enhancement, always as adjunctive to
a dual challenge of treating not only patients’ brains but also pharmacological treatment. This integrative approach combines
their bodies. Interventions targeting healthy habits (including the main components of different treatments to cover broader
nutrition and exercise) are expected to benefit patients with therapeutic objectives, to improve the prognosis of the disease in
BD. One RCT examined the effects of a 20-week CBT interven- both clinical and functional aspects, as well as the well-being and
tion (NEW tx) for BD consisting of 3 modules: nutrition, exer- QoL of those who suffer from BD (Reinares, Martínez-Arán and
cise, and wellness (Sylvia et al., 2013); patients who underwent Vieta, in press). Due to the characteristics of the intervention (12
the treatment showed improvements in nutritional habits, sessions of 90 minutes each), in case it shows its efficacy, it could
exercise, depressive symptoms, and overall functioning. Hence, be easily implemented in routine clinical care.
this study provides preliminary evidence that improving nutri-
tion and promoting an active lifestyle is associated with func-
Personal Recovery: Well-being and QoL
tional improvement and mood symptoms in patients with BD.
Another previous study showed the efficacy of an intervention Subjective assessments and patient-reported outcomes are gaining
on healthy lifestyle, nutrition, and physical exercise on muscle ground in the field of BD (Morton et al., 2017; Bonnín et al., 2018b).
mass index, particularly in women (Gillhoff et al., 2010). These As in psychosocial functioning, the problem with subjective meas-
lifestyle interventions are promising since they demonstrate ures is the variability in the definitions and in the instruments to
that people with BD can engage and be successful in these types assess the subjective experience of these patients (Morton et al.,
of therapies. Therapeutic mechanisms of action are still un- 2017). It is common that terms such as QoL, well-being or life satis-
known but might include different pathways, for example, by faction are used as synonyms and interchangeable terms (Morton
reducing morbidity (i.e., depressive symptoms), which in turn et al., 2017). Moreover, the current lack of consensus between these
would improve functional outcome (Ernst et  al., 2006), or by construct definitions add uncertainty and complication to select
enhancing treatment effects, including the synergistic effects an appropriate instrument to measure this dimension. Despite
of exercise in combination with other treatments. For instance, all, the subjective experience should always be taken into account
in schizophrenia there is some preliminary evidence suggesting since it can also impact on the course of the illness. Some studies
that cognitive remediation efficacy can be enhanced by aerobic indicate that the improvement in well-being provides a protective
472 | International Journal of Neuropsychopharmacology, 2019

effect against recurrence (Keyes et al., 2010), and it has also been Involving the family, O’Donnell and colleagues (2017) tested
found that low levels in QoL are associated with an increase in oxi- the effect of 2 psychological interventions on QoL scores in a
dative stress (Nunes et al., 2018). For this reason, it is important to sample of adolescents with BD. They compared the efficacy of a
evaluate not only objective outcomes (symptoms and functioning) FFTplus pharmacotherapy vs brief psychoeducation plus pharma-
but also to assess patients’ subjective experience, since they can cotherapy on self-related QoL over 2  years. They found the 2
provide valuable information and might be an essential part to en- groups did not differ in overall QoL scores at 24 months follow-up.
sure better outcomes in BD. However, adolescents who received the FFT had greater improve-
ments in quality of family relationships and physical well-being
compared with the brief psychoeducation program. Besides,
Pharmacological Interventions
internet-based approaches using smartphones are gaining trac-
Rajagopalan et  al. (2016) tested the effects of lurasidone as tion (Lauder et al., 2015; Hidalgo-Mazzei et al., 2018), representing
monotherapy or as adjunctive to lithium/valproate on health- a useful and attractive tool especially for the young population
related QoL (HRQoL). They found that patients in both condi- with BD (Bauer et al., 2018). So far, some preliminary studies using

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tions increased HRQoL. However, this improvement was not a mobile application (SIMPLe) have reported an improvement of
independent of changes in depression, indicating that the effect biological rhythms (Hidalgo-Mazzei et  al., 2017) and increased
of lurasidone on improving patient HRQoL may act through a re- QoL and well-being (Hidalgo-Mazzei et al., 2018).
duction in depressive symptoms associated with BD. Similarly, There is much room for improvement in the field of sub-
Gonda and colleagues (2016) found that patients enhanced both jective well-being and QoL. These above-mentioned inter-
their work functional outcome and QoL after receiving prophy- ventions may shed some light regarding the path to follow.
lactic lamotrigine therapy at 6-months follow-up. In young Nevertheless, it is important to keep in mind that those patients
patients (10–17 years old) with an acute episode of bipolar de- who suffer from more depressive symptoms, irritability, and
pression, it was found that those who received olanzapine/ psychiatric comorbid conditions present lower QoL and func-
fluoxetine combination presented better QoL scores compared tional outcomes (IsHak et  al., 2012; Sylvia et  al., 2017); hence,
with those receiving placebo (Walker et al., 2017). all the strategies directed to reduce medical and psychiatric
burdens might also be useful to increase patients’ well-being
and QoL. It is also worth mentioning that some authors defend
Psychological Interventions
that QoL depends not only on clinical remission but also re-
Even though physical activity is not a psychological interven- lies on functional recovery (Vieta and Torrent, 2016). In this line,
tion itself, it is well-known for increasing well-being and QoL; poor QoL is also associated with poor occupational outcome, re-
however, the impact of this kind of interventions has been less duced academic attainment (Marwaha et al., 2013), and difficul-
studied in the field of BD. Vancampfort and colleagues (2017) ties in activities of daily life (Träger et al., 2017). Future studies
proved the effect of 150  min/wk of physical activity on phys- should include subjective measures (such as QoL, well-being) to
ical, psychological, social, and environmental QoL; those pa- better understand the relationship with these clinical variables.
tients who did not meet the established minimum (150 minutes) Figure 2 represents a brief summary of the therapies and strat-
showed lower QoL outcomes. egies that have been presented in this review.
PROVEN EFFICACY

Pharmacological agents Physical

Funconal remediaon and Pharmacological agents CBT+Psychoeducaon, including lurasidone, acvity, FFT,
some programs of cognive including lurasidone, IPSRT, NEW tx... lamotrigine, internet-based
remediaon mifepristone, EPO olanzapine/fluoxene approaches
TARGETS

Psychosocial funconing/ Personal recovery:

neurocognive performance Well-being and QoL
INTERVENTIONS
PROMISING

Treang subthreshold
depressive symptoms Mulcomponent therapies Cognive reserve Diet and exercise
(EMDR) (IRRI, Integrave therapy…) enhancement

Figure 2.  Overview of proven and promising therapies to treat bipolar disorder. CBT, cognitive behavioral therapy; EMDR, Eye Movement Desensitization and Repro-
cessing; EPO, erythropoietin; FFT, family-focused treatment; IPSRT, Interpersonal and Social Rhythm Therapy; IRRI, Integrated Risk Reduction Intervention; NEW tx,
nutrition, exercise and wellness treatment; QoL, quality of life.
Bonnín et al.  |  473

Conclusions Shire, Sunovion, Takeda, the Brain and Behaviour Foundation,

the Generalitat de Catalunya (PERIS), the Spanish Ministry of
Because the construct of psychosocial functioning is complex Science and Innovation (CIBERSAM), EU Horizon 2020, and the
and difficult to measure, it is therefore recommended to assess Stanley Medical Research Institute. The other authors declare no
it based on the combination of 3 different approaches: (1) a sub- conflicts of interest related to this manuscript.
jective assessment that involves a self-administered measure
(SDS, WHODAS 2.0, etc.), (2) a semi-objective measure including
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The authors thank the Instituto de Salud Carlos III for the polar euthymic patients: a long-term, follow-up study. J Af-
projects (PI12/01498, PI15/00330, PI17/00941) integrated into fect Disord 121:156–160.
the Plan Nacional de I+D+I (co-funded by European Regional Bonnín  CM, Sánchez-Moreno  J, Martínez-Arán  A, Solé  B,
Development Fund/European Social Fund) “Investing in your fu- Reinares  M, Rosa  AR, Goikolea  JM, Benabarre  A, Ayuso-
ture”); the CIBERSAM; and the Comissionat per a Universitats i Mateos  JL, Ferrer  M, Vieta  E, Torrent  C (2012) Subthreshold
Recerca del DIUE de la Generalitat de Catalunya to the Bipolar symptoms in bipolar disorder: impact on neurocognition,
Disorders Group (2017 SGR 1365)  and the CERCA Programme/ quality of life and disability. J Affect Disord 136:650–659.
Generalitat de Catalunya. This work has also been supported by Bonnín  Cdel  M, González-Pinto  A, Solé  B, Reinares  M,
the project SLT006/17/00357 in the “Pla estratègic de Recerca i González-Ortega  I, Alberich  S, Crespo  JM, Salamero  M,
Innovació en Salut 2016–2020.” Dr Bonnin would like to thank Vieta  E, Martínez-Arán  A, Torrent  C, CIBERSAM Functional
the Department de Salut de la Generalitat de Catalunya for the Remediation Group (2014) Verbal memory as a mediator in
support through a PERIS grant (SLT002/16/00331) the relationship between subthreshold depressive symp-
toms and functional outcome in bipolar disorder. J Affect
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Statement of Interest
Bonnin  CM, Torrent  C, Arango  C, Amann  BL, Solé  B, González-
Dr Vieta has received grants and served as consultant, ad- Pinto A, Crespo JM, Tabarés-Seisdedos R, Reinares M, Ayuso-
visor, or CME speaker for the following identities: AB-Biotics, Mateos JL, García-Portilla MP, Ibañez Á, Salamero M, Vieta E,
Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Martinez-Aran  A, CIBERSAM Functional Remediation Group
Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest (2016) Functional remediation in bipolar disorder: 1-year
Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, follow-up of neurocognitive and functional outcome. Br J
Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Psychiatry 208:87–93.
474 | International Journal of Neuropsychopharmacology, 2019

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