bipolar

REVIEWpublished: 07 April 2015

doi: 10.3389/fphys.2015.00108

Frontiers in Physiology | www.frontiersin.org 1 April 2015 | Volume 6 | Article 108

Edited by:Anas Baudot,

Centre National de la RechercheScientifique, France

Reviewed by:KP Su,

China Medical University, TaiwanMiguel Ruiz-Veguilla,

Universidad de Sevilla/CSIC, Spain

*Correspondence:Vicent Balanz-Martnez,

Teaching Unit of Psychiatry andPsychological Medicine, Department

of Medicine, University ofValencia-CIBERSAM,

Avda Blasco Ibez, 15,46010Valencia, [email protected]

Specialty section:This article was submitted to Systems

Biology, a section of the journalFrontiers in Physiology

Received: 24 January 2015Accepted: 17 March 2015Published: 07 April 2015

Citation:Balanz-Martnez V, Crespo-Facorro

B, Gonzlez-Pinto A and Vieta E(2015) Bipolar disorder comorbid with

alcohol use disorder: focus onneurocognitive correlates.

Front. Physiol. 6:108.doi: 10.3389/fphys.2015.00108

Bipolar disorder comorbid withalcohol use disorder: focus onneurocognitive correlatesVicent Balanz-Martnez 1*, Benedicto Crespo-Facorro 2, Ana Gonzlez-Pinto 3 andEduard Vieta 4

1 Teaching Unit of Psychiatry, Deparment of Medicine, School of Medicine, La Fe University and Polytechnic Hospital,University of Valencia, CIBERSAM, ISNPR, Valencia, Spain, 2 Department of Psychiatry, School of Medicine, UniversityHospital Marqus de Valdecilla, University of Cantabria-IDIVAL, CIBERSAM, Santander, Spain, 3 lava University Hospital,CIBERSAM, University of the Basque Country, Kronikgune, Vitoria, Spain, 4 Barcelona Bipolar Disorders Program, Institute ofNeurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain

Bipolar disorder (BD) and alcohol use disorders (AUDs) are usually comorbid, andboth have been associated with significant neurocognitive impairment. Patients with theBD-AUD comorbidity (dual diagnosis) may have more severe neurocognitive deficits thanthose with a single diagnosis, but there is paucity of research in this area. To explorethis hypothesis more thoroughly, we carried out a systematic literature review throughJanuary 2015. Eight studies have examined the effect of AUDs on the neurocognitivefunctioning of BD patients. Most studies found that BD patients with current or pasthistory of comorbid AUDs show more severe impairments, especially in verbal memoryand executive cognition, than their non-dual counterparts. Greater neurocognitivedysfunction is another facet of this severe comorbid presentation. Implications for clinicalpractice and research are discussed. Specifically, the application of holistic approaches,such as clinical staging and systems biology, may open new avenues of discoveriesrelated to the BD-AUD comorbidity.

Keywords: bipolar disorder, comorbidity, addiction, alcohol use disorders, neurocognition, staging, systemsbiology

Neurocognitive Dysfunction is a Core Feature of Bipolar Disorder

Bipolar disorder (BD) is associated with signicant morbidity, premature mortality and func-tional disability (Salomon et al., 2013; Conus et al., 2014). The major sources of this disabilityseem to be episode density, psychotic features, subclinical depression, sustained neurocognitivedecits, comorbidities, medication side eects, low premorbid functioning and weak social support(Sanchez-Moreno et al., 2009a).

It is well established that BD is associated with neurocognitive decits that persist intoeuthymia after episode resolution, and thus represent a core symptom of the illness (Balanz-Martnez and Dias, 2013). Several meta-analysis have revealed impairments in the broad domainsof attention, processing speed, verbal memory and executive functions, with relative preserva-tion of verbal abilities and intelligence (Torres et al., 2007; Bora et al., 2009; Bourne et al.,2013). This pattern of decits is similar to that in schizophrenia (SZ), although less severein magnitude (Daban et al., 2006; Snchez-Morla et al., 2009). The variability in the degreeand pattern of cognitive functioning among BD patients is also more pronounced than in

Balanz-Martnez et al. Bipolar-alcohol comorbidity and neurocognition

SZ, and it has been estimated that 3060% of euthymic BDpatients show clinically relevant decits (Martino et al., 2008).Moreover, in population-based studies, BD has been associatedwith increased risk for later development of dementia, especiallyin middle-age adults (Wu et al., 2013). This risk seems to increasewith the number of episodes (Kessing and Andersen, 2004) and isindependent of confounding variables such as comorbidities (Wuet al., 2013).

There is also growing evidence that neurocognitive impair-ments are major predictors of BD patients long-term functionaloutcomes (Tabars-Seisdedos et al., 2008; Wingo et al., 2009).Therefore, neurocognitive improvement represents a therapeu-tic target in BD (Fuentes-Dur et al., 2012). There is pressingneed to develop interventions specically addressed to amelio-rate these decits by means of pro-cognitive medications (Diaset al., 2012) and cognitive training and rehabilitative strategies,such as functional remediation (Torrent et al., 2013).

Persistent neurocognitive decits (Balanz-Martnez et al.,2005) likely result from the combination of genetic and envi-ronmental risk factors, as well as neurodevelopmental and neu-roprogressive processes (Goodwin et al., 2008). Neurocognitiveimpairment may increase with illness progression (Robinson andFerrier, 2006; Bourne et al., 2013) and history of psychotic symp-toms (Selva et al., 2007; Martnez-Arn et al., 2008; Brissos et al.,2011), but it is also found in healthy rst-degree relatives ofpatients with BD, although at a lesser degree (Arts et al., 2008;Balanz-Martnez et al., 2008). Subsyndromal depressive symp-toms, comorbidites and side eects of medications may com-pound and further worsen these decits yet cannot fully explainthem (Balanz-Martnez et al., 2010).

The relative contribution of psychiatric comorbidities to BDpatients neurocognition has received limited attention. Dualdiagnosis is the concomitant or comorbid presentation of a sub-stance use disorder (SUD) or an alcohol use disorder (AUD)and another psychiatric condition. Patients with dual diagnosisrepresent a clinical population of special interest because BD ishighly comorbid with addictions (Cerullo and Strakowski, 2007;Schoepf and Heun, 2014) and prolonged heavy use of alcoholand other substances is associated with persistent neurocogni-tive and brain abnormalities (Cunningham and McCambridge,2012). Clearly, this relevant issue requires further examination.

The BipolarAlcohol Comorbidity

Several epidemiological and clinical studies have consistentlyfound high rates of comorbid AUD (i.e., alcohol abuse or depen-dence) among BD patients (Merikangas et al., 2007; Mitchellet al., 2007; Oquendo et al., 2010). Indeed, BD is the DSM Axis Idisorder most strongly associated with AUDs (Regier et al., 1990;Kessler et al., 1997). In a recent meta-analysis, lifetime preva-lence of AUDs aected approximately one third of BD patients,with higher rates in male (44%) than in female (22%) patients(Di Florio et al., 2014). Overall, patients with addictions are 56times more likely to have a history of BD compared to the gen-eral population (Kessler et al., 1997). Research has identied threesubgroups of patients, presenting with AUD rst, BD rst, and

both simultaneously. BD preceded by addiction may represent amilder illness form (Pacchiarotti et al., 2009).

Although the etiology of the BD-AUD comorbidity is poorlyunderstood, several explanations have been put forward. BothBD and AUD are complex-trait conditions with overlappingetiopathophysiological pathways at the genetic, neurochemical,neurophysiologic and neuroanatomic levels (Farren et al., 2012).Shared genetic basis could confer risk for both BD and AUD(Johnson et al., 2009). Interestingly, this common genetic vul-nerability would not be entirely driven by confounders, such asliability for anxiety disorders (Carmiol et al., 2014). Moreover,comorbid alcohol and substance use may also be a coping strat-egy by which patients try to manage (e.g., by self-treatment) theirmood symptoms (Bizzarri et al., 2009; Do and Mezuk, 2013). BDand addictions may share common mechanisms, including highimpulsivity, executive dysfunction, susceptibility to behavioralsensitization to stressors, as well as poor modulation of motiva-tion and responses to rewarding stimuli (Swann, 2010; Tolliverand Hartwell, 2012). Indeed, high trait impulsivity may medi-ate some severe manifestations of this comorbidity (Swann et al.,2009; Nery et al., 2013).

At the clinical level, dual diagnosis seems to be mutuallydetrimental since addiction worsens the clinical presentation,course, prognosis and treatment of BD, and vice versa (Salloumand Thase, 2000). Compared to BD patients without addictions,dually diagnosed patients have earlier age of onset, poor treat-ment adherence and treatment response, longer and more fre-quent mood episodes and hospitalizations, more mixed episodesand rapid cycling, more comorbid anxiety disorders and greaterimpulsivity, and higher rates of aggressive behavior and suicideattempts (Swann, 2010; Tolliver and Hartwell, 2012; Nery et al.,2013). Comorbid addictions worsen functioning in BD, some-times to that of SZ patients (Jaworski et al., 2011). Clearly, dualBD represents a prevalent, severe and dicult to treat subgroupof BD, but, surprisingly, little is known about its neurobiologicaland neurocognitive correlates (Nery et al., 2011).

The Neurocognitive DysfunctionAssociated with Alcohol Use Disorders

Chronic alcoholism exerts harmful eects on brain health andcognition, including signicantly decreased cortical thickness(Momenan et al., 2012). In addition to brain atrophy, enlarge-ment of the ventricles and sulci, as well as reductions in cerebralblood ow and glucose metabolism, particularly in prefrontalareas, have been described (Gupta andWarner, 2008). Moreover,chronic alcohol misuse has been consistently associated withwidespread neurocognitive decits, including episodic memory,attention, processing speed, visuospatial and motor abilities, ver-bal uency, and executive functions, such as decision-making,problem-solving, workingmemory, andmental exibility (Stavroet al., 2013; Bernardin et al., 2014). According to a recent meta-analysis, all these decits were of moderate magnitude and IQwas the only domain not signicantly aected by chronic alco-holism (Stavro et al., 2013). As many as 50-80% of patientsshow neurocognitive impairment, although there exists marked



inter-individual variability in the nature and the severity ofdecits (Bates et al., 2002; Bernardin et al., 2014). For instance,treatment-resistant heavy drinkers have more severe executivedysfunctions (Wollenweber et al., 2014). In the most severe andchronic cases, the clinical presentationmay be dominated by cog-nitive features, such as confabulation, amnesia and confusionalstates (e.g., Wernicke-Korsako syndrome), as well as globalcognitive deterioration (e.g., alcohol-related dementia).

Prospective studies suggest that abstinence from alcoholresults in partial neurocognitive recovery, especially regardingsustained attention (Schulte et al., 2014). Overall, a widespreadpattern of impairment seems to remain stable during the rst yearof sobriety and neurocognitive performance tends to normalizeonly after 1 year of abstinence (Stavro et al., 2013). However, cer-tain functions, such as visuospatial abilities, may remain persis-tenly impaired even after longer periods of abstinence (Bernardinet al., 2014). Therefore, several memory rehabilitation strategieshave been developed, although the eld is still in its infancy(Svanberg and Evans, 2013).

Here we aim to review the literature that has examined the rel-ative contribution of AUDs to the neurocognitive functioning ofBD patients. Since both BD and AUDs have been associated withneurocognitive impairment on their own, patients with the BD-AUD comorbidity (e.g., dual diagnosis) may have more severeneurocognitive decits than those with a single diagnosis.

To explore this hypothesis more thoroughly, we car-ried out a systematic literature review. Electronic databases(PubMed, Scopus, EMBASE) were searched through January2015 using combinations of the following search terms: bipo-lar disorder cross-referenced with cognition, neurocogniti orneuropsycholog cross-referenced with alcohol use disorder, alco-hol abuse or alcohol dependence. These searches retrieved 23,63, and 389 hits, respectively. In addition, the reference listsof relevant papers were manually checked for further articlesnot previously identied. Studies comparing neuropsychologicalperformance of BD subjects with/without AUDs were selected.

The Relative Contribution of ComorbidAlcohol Use Disorders

So far, only eight studies met the selection criteria and have com-pared the neurocognitive functioning of BD patients with andwithout comorbid AUDs (van Gorp et al., 1998; Levy et al., 2008,2012; Sanchez-Moreno et al., 2009b; van derWerf-Eldering et al.,2010; Shan et al., 2011; Chang et al., 2012; Marshall et al., 2012).The major characteristics of these studies are shown in Table 1.

In a pioneer work, van Gorp et al. (1998) examined 12 BDpatients with past history of alcohol dependence, 13 BD patientswithout such comorbidity, and 22 healthy controls. Only maleswere recruited and all outpatients were euthymic at the time ofneurocognitive assessment. Both BD groups showed verbal mem-ory decits, whereas only the dual group had an additional exec-utive decit measured by the number of completed categoriesin the Wisconsin Card Sorting Test (WCST). Moreover, neu-rocognitive functioning was negatively correlated with lifetimeduration of manic or depressive episodes, suggesting that patientswith greater illness burden had poorer performances.

Interestingly, it took one decade for the eld to revisit thistopic. Levy et al. (2008) compared three groups of BD-I inpa-tients, who were admitted mostly due to manic episodes. A rstgroup with current alcohol dependence (n = 13), a second groupin full remission (e.g., during at least 1 year) from alcohol depen-dence (n = 9), and a third non-dual group without history ofSUDs (n = 41). Those with current alcohol dependence were sig-nicantly more impaired than the non-dual group in measuresof visual memory and verbal memory. Moreover, both dual BDgroups performed signicantly worse than non-dual BD patientson executive functions measured by the Stroop test and WCST.These ndings would suggest that the BD-AUD comorbidity isassociated with more severe mnemonic and executive dysfunc-tion, and that the neurocognitive consequences of past AUDsmay persist despite sustained abstinence from alcohol. However,the presence of subacute, residual mood symptoms during exam-ination before hospital discharge may increase the severity ofdecits found in this study.

Another study by the same research group focused on cog-nition during the course of early remission from a severe moodepisode (Levy et al., 2012). This 3-month, follow-up study com-pared 21 BD patients with AUDs in the previous year and 34 BDpatients without a history of SUDs. Dually diagnosed patientsperformed worse on measures of verbal memory, visual mem-ory, and executive functioning on both assessments and showeda poorer neurocognitive recovery relative to those without SUDs.These ndings underscore the special needs of BD-AUD patientsin terms of intensive treatment and support aimed to achieveearly recovery after relapses. To that end, detailed and serial neu-ropsychological evaluations during this critical period remain asa backbone.

Consistently, another study (Sanchez-Moreno et al., 2009b)found that euthymic BD patients with (n = 30) and without(n = 35) previous history of AUDs performed poorer thanhealthy controls (n = 35) in verbal memory and executive func-tions, regardless alcohol history. However, patients with previousalcohol misuse were more impaired in the Stroop interferencetask, suggesting greater diculties in the inhibitory control ofinadequate behaviors, which may be related to higher impulsiv-ity and probably to higher risk of other addictive behaviors. Dualpatients were requested to be abstinent for at least 1 year buttime of abstinence was not recorded. BD-II patients were alsorecruited, and this is particularly relevant since type II is also sig-nicantly associated with neurocognitive impairments and AUDs(McElroy et al., 2001; Sol et al., 2012).

In this regard, a Taiwanese study focused only on type-IIBD (Shan et al., 2011). The authors compared 19 patients withcomorbid AUD, 28 patients without comorbid AUD, and 22healthy controls. All participants were alcohol-free at least 24 hbefore examination and BD patients were euthymic. Comparedto the other two groups, dual patients performed signicantlyworse on tasks of visual memory, verbal memory, attention,psychomotor speed, and executive functioning. In addition,working memory was impaired in both BD groups, althoughmore so in dual patients. However, the clinical groups werenot balanced regarding gender, educational level and numberof hospitalizations, so a potential inuence of these relevant



TABLE

1|M

ainch

aracteristicsofstud

iesinclud

edinthereview

.

Study

Coun

try

Sam

pledescription

Measuresofalco

holconsum

ption

Urine

screen

ingtest

toexclud

eother

SUDs

Specificco

mmen

ts

TypeofBD

Pha

seofBD

vanGorpet

al.,

1998

USA

25BD(type

nots

pecified)

-12

with

past

AD

-13

withou

tAD

22HC

Allpa

tientseu

thym

ic(HRSD

bipolar

Documents