Bipolar disorder and gambling disorder comorbidity: Current evidence and implications for pharmacological treatment

Journal of Affective Disorders 167 (2014) 285–298

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Review

Bipolar disorder and gambling disorder comorbidity: Current evidence and implications for pharmacological treatment Marco Di Nicola a,b,n, Luisa De Risio a, Mauro Pettorruso a, Giulio Caselli a, Franco De Crescenzo a,c, Kevin Swierkosz-Lenart d, Giovanni Martinotti e, Giovanni Camardese a, Massimo Di Giannantonio e, Luigi Janiri a,b a

Institute of Psychiatry and Clinical Psychology, Catholic University of Sacred Heart, Rome, Italy University Consortium Humanitas, Rome, Italy c Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy d Centre neuchâtelois de psychiatrie, République et Canton de Neuchâtel, Switzerland e Department of Neuroscience and Imaging, Institute of Psychiatry, “G. d’Annunzio” University of Chieti-Pescara, Italy b

art ic l e i nf o

a b s t r a c t

Article history: Received 24 December 2013 Received in revised form 12 June 2014 Accepted 12 June 2014 Available online 19 June 2014

Background: The co-occurrence of bipolar disorder (BD) and gambling disorder (GD), though of clinical and public health importance, is still scarcely investigated. Comorbid BD–GD subjects experience a more severe course of illness and poorer treatment outcome, due to a range of clinical and psychosocial factors that collectively impede remission and recovery. The aim of our paper is to review the role of pharmacotherapy in the treatment of comorbid BD–GD, in order to support clinical decisions according to the best available evidence. Methods: A qualitative systematic review of studies on pharmacological treatment in comorbid BD–GD was performed. A comprehensive literature search of online databases, bibliographies of published articles and gray literature was conducted. Data on efficacy, safety and tolerability were extracted and levels of evidence were assessed. We also provide a brief overview of current epidemiological, neurobiological and clinical findings, with the intention of proposing a dimensional approach to the choice of available drugs. Results: The only drug with a high level of evidence is lithium. Considering the inclusion of GD in DSM-5 ‘Substance-related and Addictive Disorders’ category, we discuss the use of other drugs with a high level of evidence currently used in BD subjects with co-occurring substance use disorders. Limitations: Only few clinical trials are available and the population is limited; therefore no conclusive evidence can be inferred. Conclusions: Further randomized controlled trials are required to evaluate the efficacy of pharmacological treatment strategies in large samples of patients with comorbid BD–GD. Also, attempts should be made to identify other shared clinical and psychopathological domains that are amenable to treatment. & 2014 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder Gambling disorder Comorbidity DSM-5 Addictive behaviors Pharmacological treatment

Contents 1. 2. 3. 4. 5. 6.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Epidemiology and risk factors for BD–GD comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Genetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Clinical and neuropsychological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Systematic review of pharmacological treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 6.1. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 6.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 6.2.1. Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

Corresponding author at: Institute of Psychiatry and Psychology, Catholic University of Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy. Tel.: þ39 0630154121. E-mail address: [email protected] (M. Di Nicola).

http://dx.doi.org/10.1016/j.jad.2014.06.023 0165-0327/& 2014 Elsevier B.V. All rights reserved.

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6.2.2. Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 6.2.3. Atypical antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 6.2.4. Opioid antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 6.2.5. Glutamatergic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 6.2.6. Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

1. Introduction Bipolar disorder (BD) is a severe, often chronic condition with lifetime prevalence rates of up to 6.5% in the general population (Vornik and Brown, 2006). The co-occurrence of other psychiatric disorders in bipolar patients is associated with several indices of illness severity, a low probability of recovery as well as an unfavorable course and outcome (McIntyre et al., 2004). BD patients frequently report co-occurring substance use disorders (SUDs) and behavioral addictions (Di Nicola et al., 2010a; Pettorruso et al., 2014b), including gambling disorder (GD). GD is characterized by persistent and maladaptive gambling behavior, whereby individuals engage in frequent and repeated episodes of gambling despite serious adverse consequences (Hodgins et al., 2011). GD affects 0.5–1% of adults worldwide; the consequences of this behavioral disturbance often entail severe damage to the lives of patients and their families (Kessler, 2008). There is strong evidence suggesting that similar predispositions (genetic, environmental and social) influence the development and maintenance of GD and addictive disorders (Potenza, 2008). Also, like SUDs, GD presents the phenomena of tolerance, withdrawal and craving. The DSM-5 included GD in the diagnostic category of ‘Substance-related and Addictive Disorders’ (APA, 2013). Pathophysiological models for drug addiction may therefore be relevant to GD as well and GD patients which may benefit from medication used to treat SUDs (Potenza, 2008). The co-occurrence of BD and GD has important clinical implications. As in BD patients with co-occurring SUDs, BD–GD patients experience a more severe course of illness and poorer treatment outcome, due to a range of clinical and psychosocial factors that collectively impede remission and recovery (Mazza et al., 2009; Kennedy et al., 2010; Mandelli et al., 2012).

2. Epidemiology and risk factors for BD–GD comorbidity To date, there are relatively few population-based epidemiological studies that report on the prevalence, and associated features, of GD in bipolar patients. With regard to GD sample studies, Lorains et al. (2011) found that GD patients have significantly more axis I disorders than controls, with higher rates of BD (12.6%). Prevalence of GD was significantly higher (6.3%) amongst BD subjects as compared to the general population (2.0%) and major depressed patients (2.5%) (McIntyre et al., 2007). The prevalence of GD in a large sample of individuals with a lifetime history of a mood disorder who were not seeking treatment for GD was 4–5% according to conservative criteria and 10–11% according to liberal criteria. Kennedy et al. (2010) report that liberal GD prevalence estimates are comparable to those obtained for individuals seeking treatment for BD (12.3%). Both conservative and liberal estimates are significantly higher than the estimates reported within the

general population, thus indicating that individuals with BD are six times more likely to meet criteria for GD (Cox et al., 2005). A significant difference in prevalence rates of BD–GD comorbidity was observed between males (19.5%) and females (7.8%) (Kennedy et al., 2010). Alcohol dependence, along with other SUDs, conferred the highest risk for GD in BD patients. BD patients who met criteria for GD had significantly higher levels of somatic anxiety and of clinician-rated depression (Kennedy et al., 2010). These findings have relevant implications for the recognition of BD subjects at a high risk of developing GD. It has been suggested that mood and anxiety disorders often precede gambling problems (Petry et al., 2005; Kennedy et al., 2010). Also, a recent longitudinal, prospective study found that subjects who reported past-year disordered gambling were significantly more likely to have new onset of axis I psychiatric disorders, including mood disorders (Chou and Afifi, 2011). The relationship between GD and mood disorders is not, however, necessarily causal (Quilty et al., 2011). In pathological gamblers, the co-occurrence of other mental disorders increases the likelihood of treatment-seeking, though it may be the case that GD subjects are more likely to seek treatment for their comorbid disorders rather than for their gambling problems, which thus go undetected (Winters and Kushner, 2003). Opportunistic screening for GD is warranted, particularly in BD patients with comorbid alcohol or substance dependence.

3. Genetic Familial and illness course characteristics of BD and addictive disorders, as well as shared or similar underlying mechanisms involving impulsivity, reward and behavioral sensitization, suggest potentially important genetic overlap (Swann, 2010; Mandelli et al., 2011). Despite high comorbidity rates between BD and GD, the literature lacks studies specifically investigating common genetic determinants, but preliminary findings hint at the existence of a shared genetic vulnerability for GD and SUDs (Uhl et al., 2008). Comparing data between bipolar and control samples, Johnson et al. (2009) found convergent genome wide association results for BD and SUDs. Products of one group of these genes are likely to play substantial roles in the initial and/or plasticity-related “wiring” of the brain (semaphorin 5A, slit homolog 3, CUB, Sushi domains, neuron navigator 2, cadherin 13) (Johnson et al., 2009). A second group of genes is the family of clock genes, implicated in the regulation of behavioral and physiological periodicity (Swann, 2010).

4. Neuroimaging Structural imaging studies in patients with comorbid BD–GD found volume reductions in both the dorsal and ventral prefrontal cortex (PFC), which are involved in encoding incentive information used to influence behavioral responses (Wallis and Miller, 2003;

M. Di Nicola et al. / Journal of Affective Disorders 167 (2014) 285–298

Haldane and Frangou, 2004). During a gambling task (Iowa gambling task, IGT), BD patients showed abnormalities in the dorsal and ventral PFC, while lateral temporal and polar regions displayed increased activation (Frangou et al., 2008). Jogia et al. (2012) confirmed these observations and also reported a greater activation in the anterior cingulate cortex of BD patients performing the IGT and in the insula during the n-back working memory task. Moreover, in GD patients, Kertzman et al. (2006) found diminished performance on the Stroop Test, a task reflecting anterior cingulate function and indicating diminished ability to modulate irrelevant information. Stroop activation deficits have similarly been reported in BD patients (Marchand et al., 2007). In a FDG-PET study in 21 GD patients, who met lifetime comorbid bipolar spectrum diagnosis, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to controls (Hollander et al., 2008). Baseline metabolic hyperactivity in PFC areas may be interpreted as a compensatory mechanism, a way of coping with functional impairment through the recruitment of an alternative neural network. The authors also found that lithium administration was associated with widespread effects on the PFC and cingulate gyrus. GD subjects with comorbid bipolar spectrum diagnosis also showed decreased rGMR in the ventral parts of the striatum and thalamus and increased rGMR in the dorsal parts, as compared to controls. Because of their extensive connectivity to the frontal cortex, striatal and thalamic functional alterations may contribute to faulty decision-making processes in pathological gamblers (Pallanti et al., 2010). To date, no studies have specifically investigated the dopaminergic system in comorbid BD–GD patients. Reduced functioning of the dopamine transporter (DAT) has been linked to BD (Young et al., 2011; Camardese et al., 2014). Genetic alteration of the D2 receptor has also been implicated in a range of addictive, impulsive and compulsive disorders, including GD (Comings et al., 1996). Animal models may provide insight into the role of the dopaminergic system in risk-taking and gambling behavior. Mice with reduced DAT functioning exhibit a behavioral profile consistent with manic patients and increased risk-taking behavior during a mouse version of the IGT (Young et al., 2011). Evidence from these animal model studies allows us to hypothesize that system-related change involving functioning of the DAT play a role in impulsive choice, risk-taking behavior and reward, and this may help guide future studies in BD–GD subjects (van Enkhuizen et al., 2013).

5. Clinical and neuropsychological features With respect to BD and GD, community-based epidemiology, phenomenology, associated psychopathology and high rates of suicidality are some major overlapping areas (McElroy et al., 1996). Even though the relationship between these disorders is not fully understood, the complex underlying pathophysiological mechanisms involved in each disorder possibly cross clinical diagnostic boundaries (Kim et al., 2006). GD symptoms are frequently accompanied by affective symptoms that resemble those of bipolar disorder. Urge to gamble is often associated with arousal and restlessness that resemble the elevated mood or with tension and anxiety, similar to that which can occur in depressive or mixed states (Cunningham-Williams et al., 2009). Various forms of emotional and mood disturbance are associated with divergent motivations that might represent distinct pathways into gambling behavior (Lloyd et al., 2010). Manic/hypomanic symptoms concern at least one fourth of the GD population. GD patients who experience hypomanic symptoms report stronger motivations to gamble as a means to regulate

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mood, more frequently to gain pleasure and enjoyment. Symptoms of GD and gambling behavior in mania share some similarities, especially with respect to feelings of lack of control over impulsivity. Also, both conditions present with similar types of behavior, generally involving harmful, dangerous and rewardseeking behaviors (McElroy et al., 1996). Depressive symptoms are also a very common finding among pathological gamblers, and evidence suggests that they are closely related to engagement in gambling. Depressive symptoms predicted gambling urge and duration in a sample of slot machine addicted individuals (Rømer Thomsen et al., 2009). Depressive symptoms possibly provide an impetus to console or comfort oneself through gambling, as an attempt to relieve a negative mood (Shead and Hodgins, 2009). Anxiety symptoms are commonly associated with both BD and GD. Consistent with an addiction model, it has been proposed that gamblers who experience high levels of anxiety engage in gambling activities to reduce arousal states. Furthermore, anxiety symptoms have been considered as part of withdrawal-like symptoms in GD (Smith et al., 2011). Impulsivity, poor modulation of motivation and of response to rewarding stimuli, as well as susceptibility to behavioral sensitization are some other mechanisms linking BD and GD (Swann, 2010). Indeed, GD may mask bipolar spectrum disorders that primarily manifest themselves with difficulty in impulse control (Lejoyeux, 2005). Likewise, the role of bipolar features in the addictive process is often overlooked, since attenuated and subthreshold bipolar psychopathology is often not adequately recognized (Kim et al., 2006; Maremmani et al., 2006). Impulsivity is a core feature of BD and a hallmark of GD. Accordingly, in BD patients, high trait impulsivity was associated with the occurrence of behavioral addictions (Di Nicola et al., 2010a). BD and GD also share compulsive features, though research on compulsivity is not as developed as it is for impulsivity (el-Guebaly et al., 2012; Leeman and Potenza, 2012). Studies indicate that pathological gamblers score highly on specific measures of compulsivity, and it seems that, over time, impulsive habitual responding in GD may shift toward a more compulsive pattern of behavior (Potenza, 2008; Blanco et al., 2009). Behaviors in GD patients are often repetitive and hard to suppress. Also, most published findings suggest heightened response perseveration in GD (Goudriaan et al., 2005; Marazziti et al., 2008; de Ruiter et al., 2009). Bipolar patients display relevant anhedonia during depressive states, and recent evidence points to the presence of residual anhedonic features during the euthymic phase (Di Nicola et al., 2013), suggesting that low hedonic capacity could represent an enduring trait of BD. Moreover, numerous studies assert that anhedonia plays an important role in substance dependence, both as part of withdrawal syndromes and as a relevant factor involved in relapse (Martinotti et al., 2008). It has recently been hypothesized that anhedonia is also relevant to GD (Pettorruso et al., 2014c); some authors describe an association between presence of anhedonic symptoms and gambling urge (Rømer Thomsen et al., 2009). Craving phenomena, defined as the subjective urge to consume a drug or behave in a certain way, and abnormal cue reactivity are central to addictive behaviors and may promote relapse. As in all substance and behavioral addictions, craving is a key symptom of GD as well; research on relapse precipitants suggests that craving is one of the main factors to provoke and maintain episodes of gambling (Ashrafioun and Rosenberg, 2012). Neuroimaging studies indicate that brain regions involved in mood regulation lie in close proximity to regions that process motivation and craving. Higher susceptibility to craving phenomena (eating dysregulation, craving for activity or exercise), in fact, has also been observed in BD patients (McElroy et al., 2005). Growing evidence suggests that BD and GD patients are both characterized by significant neurocognitive impairment. BD patients

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experience alterations in cognitive skills (deficits in attention, episodic memory, executive functioning) during both acute mood episodes and euthymic states (Martínez-Arán et al., 2004); persistence of neurocognitive impairment during euthymia indicates that it is an enduring feature of BD that significantly affects judgment and functioning even during inter-episodic phases (Wingo et al., 2009). In a meta-analytic study comparing neurocognitive performance in euthymic bipolar patients and matched controls, significant deficits in measures of executive functions, verbal learning, immediate and delayed verbal memory, abstraction, sustained attention and psychomotor speed were observed (Robinson et al., 2006). Verbal learning/memory and verbal working memory have even been proposed as neurocognitive endophenotypes in BD (Balanzá-Martínez et al., 2008). Further, BD patients showed trait impairment in risk-sensitive decisionmaking, as assessed with the IGT and an index of sensitivity to punishment frequency (Adida et al., 2011; Ibanez et al., 2012). In GD, research has identified cognitive deficits in a variety of domains, and attempts have been made to devise treatment strategies that specifically target cognitive symptoms (Grant et al., 2010a; Fortune and Goodie, 2012). Pathological gamblers often have difficulty shifting their thoughts and behavior away from gambling. Enhanced cue reactivity and attentional bias to gambling cues have been reported in GD, along with increased rewardseeking behavior and lowered reward sensitivity (van Holst et al., 2010). Pathological gamblers have difficulty filtering irrelevant information and inhibiting ongoing responses (Fuentes et al., 2006; Kertzman et al., 2008). Decision-making and executive functions have also been shown to be compromised (Forbush et al., 2008). Moreover, GD patients are characterized by deficient motor response inhibition and impaired cognitive flexibility (Odlaug et al., 2011).

6. Systematic review of pharmacological treatment To date, studies on pharmacological treatment strategies for BD–GD comorbidity are rather limited and several difficulties hamper the development of reliable and effective treatment guidelines. Key limitations include lack of adequate testing in large, rigorous studies, and high prevalence of comorbidity with other psychiatric disorders (mainly SUDs and anxiety disorders) (Kennedy et al., 2010). The above-described identification of shared neurobiological dysfunctions may certainly help conceive a biological rationale for pharmacological interventions. However, knowledge on the neurobiological basis of BD–GD comorbidity is, by itself, currently insufficient to direct pharmacological treatments. The overlap between BD and GD in phenomenological and clinical terms, as well as in patterns of comorbidity, highlights the existence of a shared psychopathological framework that may also guide treatment options. We first reviewed current literature on pharmacotherapy specifically for patients with BD–GD comorbidity. However,

considering the scarcity of studies, we secondarily also focused on common underlying psychopathological dimensions (i.e., impulsivity, compulsivity, craving, obsessive–compulsive symptoms). Finally, in light of the conceptualization of GD as a form of addiction, we reviewed evidence on pharmacological interventions in BD–SUDs comorbidity and discussed their applicability to BD–GD comorbidity. 6.1. Methods A comprehensive computer literature search of the PubMed/ MEDLINE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINHAL), PsycINFO, ClinicalTrial.gov, European medicines agency databases was conducted to find relevant peer reviewed articles on clinical studies in comorbid BD–GD. Search terms included pathological gambling, bipolar disorder, comorbidity, pharmacological treatment, substance use disorders, addiction, craving. The terms were combined to elicit relevant articles. No beginning date limit was used and the search was updated through December 2013. To expand our search, references of the retrieved articles and reviews were hand-searched for additional studies. Gray literature was searched through OpenSIGLE and PsycEXTRA. There were no language limits. A level of evidence was attributed to each treatment using the classification scheme adopted by the national guidelines Clearinghouse (Shekelle et al., 1999) (Table 1). When there was no pharmacological evidence available for the treatment of comorbid BD–GD, we considered current evidence from comorbid BD–SUDs studies. The conceptualization of GD as an addictive disorder has been consistently supported and is formalized in the DSM-5 (van den Brink, 2012; Hasin et al., 2013). This literature review reports results on various drugs and then makes final treatment suggestions based on treatment outcome, level of evidence (although frequently extremely limited), and clinical support. 6.2. Results The results of our literature review are presented in Table 2, which describes studies examining pharmacological treatment specifically in comorbid BD–GD patients. In Table 3 the level of evidence for each drug in BD, GD, and comorbid BD–GD has been collected. In Fig. 1 an algorithm with a dimensional approach is proposed for the treatment of comorbid BD–GD. The following is a summary of findings. 6.2.1. Lithium Given its well-documented mood stabilizing and anti-impulsive properties as well as its acknowledged efficacy in the treatment of BD, lithium may be a viable option to treat BD–GD patients. Geller et al. (1998) reported an advantage of lithium compared with placebo in improving mood symptoms and substance use in a small, six-week, double-blind study of 25 adolescents with bipolar disorder and secondary substance use.

Table 1 Classification scheme (Shekelle et al., 1999). Category of evidence IA IB IIA IIB III IV

Evidence Evidence Evidence Evidence Evidence Evidence

from from from from from from

meta-analysis of randomized, controlled trials. at least one randomized, controlled trial. at least one controlled study without randomization. at least one other type of quasi-experimental study. non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies. expert committee reports or opinions or clinical experience of respected authorities, or both.

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Table 2 Studies on pharmacological treatment of bipolar disorder and gambling disorder comorbidity. Authors

Drug used

Mannu and Minnai, 2005 Quetiapine flexibledose 8007 135.6 mg/d Hollander et al., 2005

Nicolato et al., 2007

McElroy et al., 2008

Berlin et al., 2013

Study Design

Patient sample

Assessment Outcome measures

Results

Case series

8 BD–PG patients n ¼3 BD I n ¼5 BD II

None

Previous failure of lithium treatment. Gambling behavior abated after 8 weeks of treatment. On long-term follow-up (57 months) the patients remained asymptomatic. Reduction in: PG-YBOCS (total, thoughts/urges, behavior), PG-CGI, Clinician-Administered Rating Scale for Mania. Change in PG symptoms after 8 or more weeks of treatment. Gambling behavior abated after 2 months of combined treatment. On long-term follow up the patient remained asymptomatic.

Lithium carbonate 10-week, (Sustained-Release) doubleblind RCT 11507 215 mg/d Lithium (900 mg/d) Case report and Topiramate (200 mg/d) combination Olanzapine 12-week, 8.9 7 5.2 mg/d doubleblind, flexibledose RCT Topiramate 222.5 7 108.4 mg/ d

14-week, doubleblind RCT

PG: none. Mood symptoms: HAM-D, YMRS SCID-I, PG-CGI, PGMDQ, SOGS YBOCS, VAS for craving

PG with BD comorbidity Lithium n¼ 12 Placebo n¼ 17 57-year-old woman None with BD II and PG comorbidity PG patients (BD I excluded; BD II and BD NAS included) Olanzapine n¼ 21 Placebo n¼ 21 PG patients (BD excluded; mild depression and mania included) Topiramate n¼ 20 Placebo n¼ 22

None

SCID-I, SOGS

PG-YBOCS, CGIS, CGI-I, HDRS, YMRS, GAF

Olanzapine was not superior to placebo; it was also associated with a high discontinuation rate. No specific analysis on BD patients was conducted.

SCID-I, SCIPG, SOGS, MADRS, YMRS

PG-YBOCS, G-SAS, MADRS, YMRS, HARS, BIS-11, CGI-I

No significant treatment effect of topiramate on primary or secondary outcome measures. Reduction in BIS total score and Motor and NonPlanning subscale scores.

BGCS: Brecksville Gambling Craving Scale; BIS-11: Barratt Impulsiveness Scale – 11; CGI-I: Clinical Global Impression – Improvement; CGI-S: Clinical Global Impression – Severity of Illness Scale; DGS: Desire to Gamble Scale; GAF: Global Assessment of Functioning; G-SAS: Gambling Symptom Assessment Scale; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery–Asberg Depression Rating Scale; MDQ: Mood Disorder Questionnaire; PG-YBOCS: Yale–Brown Obsessive–Compulsive Scale for Pathological Gambling; SCI-PG: Structured Interview for Pathological Gambling; SOGS: South Oaks Gambling Screen; VAS: Visual Analog Scale; YMRS: Young Mania Rating Scale.

Table 3 Levels of evidence. Drug

BD

GD

BD–GD

Lithium

IA (Cipriani et al., 2011)

IB (Pallanti et al., 2002)

IB (Hollander et al., 2005)

Anticonvulsants Valproate Carbamazepine Topiramate Lamotrigine Gabapentin Pregabalin

IA (Fountoulakis et al., 2012) IA (Weisler et al., 2006) IB (Vieta et al., 2002) IA (Bowden and Singh, 2012) IB (Pande et al., 2000) IIB (Schaffer et al., 2013)

IB (Pallanti et al., 2002) IIB (Black et al., 2008) IB (Berlin et al., 2013; negative) NA NA NA

NA NA IV (Nicolato et al., 2007) NA NA NA

Atypical antipsychotics Olanzapine Quetiapine Aripiprazole Risperidone

IA IA IA IA

IB (McElroy et al. 2008; negative) NA NA NA

NA III (Mannu and Minnai, 2005) NA NA

Opioid antagonists Naltrexone Nalmefene

NA NA

IB (Achab and Khazaal, 2011) IB (Grant et al., 2010b)

NA NA

Glutamatergic drugs N-acetylcisteine Memantine Amantadine Acamprosate

IIB (Berk et al., 2011) III (Koukopoulos et al., 2012) IV (Ohlmeier et al., 2007) NA

IB (Grant et al., 2014) IIB (Grant et al., 2010a) IV (Pettorruso et al., 2012) IIB (Black et al., 2011)

NA NA NA NA

Antidepressants SSRIs Bupropion

IA (Gijsman et al., 2004) IB (Sachs et al., 2007)

IIB (Black et al., 2007b) IIA (Dannon et al., 2005b)

NA NA

(Cipriani (Cipriani (Cipriani (Cipriani

et et et et

al., al., al., al.,

2011) 2011) 2011) 2011)

BD ¼Bipolar disorder; GD ¼ Gambling disorder; NA ¼not assessed.

Moskowitz (1980) first reported the effectiveness of lithium in treating 3 pathological gamblers with bipolar features. Recently, Hollander et al. (2005) conducted a 10-week, double-blind, placebo-controlled treatment study of sustained-release lithium

carbonate in pathological gamblers with bipolar spectrum disorders (BD type II and cyclothymia), with primary outcome measures being PG-YBOCS and CGI scores. The lithium-treated group showed a significant improvement over the placebo group.

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Fig. 1. Proposal of an algorithm with a dimensional approach for the treatment of bipolar disorder (BD) and gambling disorder (GD) comorbidity.

Reduction in PG-YBOCS and CGI scores was significantly greater in the lithium-treated group. In the latter, less severe gambling thoughts, urges and behavior were observed. Moreover, affective instability was found to be lower and impulsivity measures also improved. Considering that reduction of gambling urges/behavior was substantial despite only minimal reduction of depressive and manic symptoms, the authors speculated that sustained mood stabilization potentially influences the cognitive substrata of impulsive gambling behavior. In a FDG-PET study, Pallanti et al. (2010) investigated the effects of lithium on brain activity in GD subjects with co-occurring BD. At baseline, GD–BD patients had a lower rGMR in the caudate nucleus compared to controls. Lithium elevated the rGMR in the caudate nucleus and alleviated some symptoms of GD. Indeed, failures in cortical control of fronto-striatal neural circuits have been shown to drive impulsive activity (Fineberg et al., 2010). Taken together, current studies provide some evidence for the use of lithium in patients with BD–GD and underscore the central role of impulsivity and affective instability in unraveling the relationship between these comorbid disorders. Lithium is the only drug with a IB level of evidence for comorbid BD–GD (Table 3).

6.2.2. Anticonvulsants Anticonvulsants are widely used in the acute and maintenance phase of BD treatment and some are of well-established moodstabilizing efficacy (Geddes and Miklowitz, 2013). They have also been extensively tested for the management of bipolar patients with comorbid SUD and some have anti-impulsive properties and have demonstrated efficacy in reducing craving and preventing relapse (Vornik and Brown, 2006). Preliminary evidence suggests that anticonvulsants may be useful in the treatment of GD and show promise in BD–GD comorbidity. Valproate. Valproate has actions on DA, GABA and Glu neurotransmission and intracellular signaling. In BD patients, it has renowned efficacy in both acute mania and maintenance treatment (Fountoulakis et al., 2012). Valproate targets core features of manic symptomatology (e.g., impulsivity, hyperactivity and irritability) (Bowden, 2007).

In patients with SUDs, valproate appears to be useful and to have anti-craving properties (Maremmani et al., 2010). Efficacy of valproate has been tested in BD patients with comorbid alcohol and substance abuse with consistent results (Hertzman, 2000; Salloum et al., 2005; Sattar, 2007). To date, few data pointing to the utility of valproate in the treatment of GD exist. Valproate was compared to lithium in a 14week, single-blind trial. The valproate-treated group received doses of 873.7 7280.1 mg/d. Primary outcome measures included PG-YBOCS and CGI scores. Both the lithium-treated group and the valproate-treated group showed significant improvement, with a 35.9% improvement on PG-YBOCS scores for patients receiving valproate (Pallanti et al., 2002). Given that the central features of impulsivity and compulsive repetition seem to be specifically targeted by valproate, its use in comorbid BD–GD patients is promising. Carbamazepine. Carbamazepine is widely used in BD and has been tested for use in ICDs as well (Weisler et al., 2006). Its mechanism of action may be related to inhibition of sodium channel activity and glutamate release. Carbamazepine has also been shown to potentiate GABAergic and DAergic neurotransmission and to inhibit kindling in the limbic system (Post and Weiss, 2011). In a single case study, Haller and Hinterhuber (1994) first reported the effectiveness of carbamazepine 600 mg daily versus placebo in a case of chronic GD. This patient had previously tried other interventions such as other pharmacological treatments (antidepressants and anxiolytics), behavioral therapy and selfhelp groups but had failed to abstain from gambling for more than three months. After treatment with carbamazepine, the patient reported abstinence for thirty months. Black et al. (2008) subsequently tested the efficacy and tolerability of extended release carbamazepine in GD in a prospective, 10-week, openlabel trial. The primary efficacy measure was the PG-YBOCS. The authors observed significant improvement in the urge component of the PG-YBOCS and conclude that carbamazepine may be effective in the treatment of GD. Though data on the use of carbamazepine in GD are preliminary, its well-established use in the treatment of BD and likely effectiveness in reducing impulsive behavior suggest it may be useful in the treatment of comorbid BD–GD.

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Topiramate. Topiramate is a glutamatergic antagonist and proGABA-ergic drug that significantly reduces impulsive behavior and compulsiveness. It has been tested and found to be effective versus placebo in disorders in which impulsivity and craving represent core features, such as alcohol dependence, cocaine dependence, bulimia nervosa and binge eating disorder (Hoopes et al., 2003; Johnson et al., 2003; Kampman et al., 2004). Moreover, a pilot study (Guille and Sachs, 2002) and a case report (Huguelet and Morand-Collomb, 2005) suggest its efficacy to reduce alcohol use disorders in bipolar patients. A 14-week, randomized, double-blind, placebo-controlled trial investigated topiramate in GD (Berlin et al., 2013). Though no significant differences between the placebo group and the topiramate-treated group were observed with respect to primary outcome measures (change in the obsessions subscale of the PG-YBOCS), topiramate reduced impulsivity (particularly, motor and nonplanning impulsivity), as measured with the Barratt Impulsiveness Scale (BIS-11). The authors suggest that topiramate could be useful in GD subgroups characterized by high levels of impulsivity. Dannon et al. (2005a) compared the effectiveness of topiramate versus fluvoxamine in the treatment of GD in a 12-week, blind-rater comparison trial. Though the authors conclude that both topiramate and fluvoxamine monotherapy may be effective in the treatment of GD, improvement on the PG-CGI for fluvoxamine did not quite reach statistical significance. Also, a larger number of drop-outs were reported in the fluvoxamine group. Topiramate's usefulness in disorders characterized by impulsivity and craving/urges suggests that it may show promise as an add-on treatment in comorbid BD–GD patients. Literature is currently limited to a single case report (Nicolato et al., 2007). This case study reported full remission of gambling craving and behavior after topiramate was added to standard lithium treatment. Lamotrigine. The role of lamotrigine in BD maintenance treatment is relatively well-established, principally as a component of a combination treatment (Bowden and Singh, 2012): it specifically showed relevant improvements in bipolar depression in off-label use in combination with lithium, carbamazepine and olanzapine (Köhler et al., 2013). Based on the hypothesis that seizure kindling-like mechanisms contribute to addiction, it has been posited that lamotrigine may be useful in the treatment of addictive behaviors as well (Crosby et al., 1991). Its action on voltage-sensitive sodium channels causes inhibition of glutamate release, which plays an important role in maintaining addiction, also via its interaction with DA (McGinty, 1995). Several authors have investigated the use of lamotrigine in patients with comorbid BD and substance abuse. Lamotrigine adjunctive therapy to lithium and valproate combination was well tolerated and effective in bipolar patients with a recent history of substance abuse and non-response to the initial treatment of lithium plus valproate (Wang et al., 2010). Lamotrigine reduced alcohol craving and consumption in BD patients with alcohol dependence (Rubio et al., 2006). An RCT tested lamotrigine use in cocaine-dependent BD patients and significant improvements in mood symptoms, cocaine craving and use were observed (Brown et al., 2012). At present, the effectiveness of lamotrigine in the treatment of GD has not been investigated. Data discussed here points to a potential utility of lamotrigine as an anti-addictive and anticraving agent. Future studies should consider and test this drug as an add-on treatment for patients with comorbid BD–GD. Gabapentin. Gabapentin modulates GABA-ergic and glutamatergic neurotransmission (Hendrich et al., 2008; Cai et al., 2012). Gabapentin is mostly used in the treatment of mood and anxiety disorders, especially in severely ill patients (Pande et al., 2000). Despite lack of efficacy in the acute phases of BD, during maintenance treatment it is used as an add-on drug in patients with poor response to monotherapy with other mood stabilizers as it

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improves residual symptoms including irritability, social withdrawal and anxiety (Vieta et al., 2000). Adjunctive gabapentin has also been shown to have prophylactic efficacy, thus improving the long-term outcome of BD (Vieta et al., 2006). The usefulness of gabapentin in resistant BD may reside in its effect on comorbid panic disorder and alcohol abuse (Perugi et al., 2002). Several authors have explored the use of gabapentin in alcohol use disorders. It reduced alcohol consumption and craving, thereby facilitating abstinence (Furieri and Nakamura-Palacios, 2007). In patients with acute alcohol withdrawal symptoms, gabapentin selectively accelerated mood improvement (Bonnet et al., 2007). Literature on the use of gabapentin in addictive disorders is still quite limited and there is some evidence on its potential for misuse particularly in subjects with a history of addiction (Smith et al., 2012). Future studies should investigate the use of gabapentin as an add-on treatment in bipolar patients with comorbid GD, given that this drug seems to specifically target the central features of impulsivity, anxiety and craving. Pregabalin. Pregabalin is a structural analog of GABA, similar to gabapentin (Taylor et al., 2007). It also reduces excitatory neurotransmitter release and post-synaptic excitability. It is a safe and effective acute and maintenance adjunctive medication for treatment-resistant BD outpatients (Schaffer et al., 2013). It appears to have mood stabilizing and antidepressant properties and is a valuable option in bipolar patients with comorbid anxiety disorders (Keck, 2006). Recent reports also suggest that it may be useful as an add-on strategy for treatment-resistant obsessive– compulsive symptoms (Di Nicola et al., 2011). Pregabalin has been studied in alcohol and benzodiazepine dependence with promising results (Martinotti et al., 2010; Di Nicola et al., 2010b; Oulis and Konstantakopoulos, 2012) even if potential abuse or misuse of the drug has been reported (Martinotti et al., 2013). In view of the mood stabilizing properties of pregabalin along with its impact on impulsive behavior and compulsive repetition, it could be useful in the treatment of comorbid BD–GD patients.

6.2.3. Atypical antipsychotics Atypical antipsychotics play an important role in the acute and maintenance treatment of BD. Robust evidence supports their use in the treatment of mania and in the prevention of manic relapse, and some atypical antipsychotics have shown efficacy in the treatment/prevention of depressive episodes. Currently, antipsychotics do not have a role in the treatment of GD (van den Brink, 2012). Only a few studies (with olanzapine) have been performed in GD patients, but none specifically relating to comorbidity with BD. Nevertheless, atypical antipsychotics have been studied in the treatment of patients with ‘dual diagnosis’, including BD (Zhornitsky et al., 2010; Beaulieu et al., 2012). In addition, some atypical antipsychotics have shown to be effective when used as augmentation in the treatment of resistant obsessive–compulsive symptoms (Skapinakis et al., 2007), though their long-term effectiveness is uncertain (Matsunaga et al., 2009). Hence, atypical antipsychotics could potentially be used to target compulsive features in BD–GD patients. We will not discuss paliperidone, ziprasidone and asenapine as, even though their use in BD treatment is well-established, to our knowledge currently no studies on their role in BD–GD and BD–SUD comorbidity are available. Olanzapine. Olanzapine is a selective monoaminergic antagonist with a strong affinity for 5-HT2A and 5-HT2C receptors, and D1, D2, D3, and D4 receptors (Bymaster et al., 1996). Two studies have examined the use of olanzapine in the treatment of GD. In a 12-week, double-blind, placebo-controlled trial on 42 pathological gamblers, olanzapine (mean dose 8.9 75.2 mg) and placebo did

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not differ significantly with respect to reduction in gambling behavior and urges (McElroy et al. 2008). Similarly, Fong et al. (2008) tested 21 GD subjects in a 7-week, double-blind, placebocontrolled trial and found comparable reductions in gambling craving and behavior in the olanzapine and placebo groups. Olanzapine has not been systematically studied in BD–SUDs patients. Only few reports indicate it decreases alcohol craving and use in BD patients with comorbid alcohol dependence (Sattar et al., 2003), especially in a subset of individuals with the longer alleles of the DRD4 genotype (Hutchison et al., 2006). Some evidence suggests that olanzapine may improve OCD symptoms in treatment-refractory patients (Maher and Theodore, 2012). Despite its consolidated role in BD treatment, current studies do not decisively support olanzapine use in patients with comorbid BD–GD. Quetiapine. Quetiapine is an antagonist at 5-HT1A, 5-HT2A, D1, D2, H1, α1 and α2 receptors (Goldstein, 1999). The efficacy of quetiapine in the treatment of BD is well-established and it has also been approved by the FDA as monotherapy in bipolar depression. Quetiapine has been tested in refractory OCD in several clinical trials, which yielded mixed but promising results (Denys et al., 2004; Carey et al., 2012). RCTs did not prove quetiapine to be effective in comorbid BD and alcohol dependence (Brown et al., 2008; Stedman et al., 2010). An RCT comparing quetiapine and risperidone for cocaine or methamphetamine use in BD found significant improvements in craving and overall drug use in both treatment arms (Nejtek et al., 2008). To date, only one study evaluated the efficacy of quetiapine in BD–GD comorbidity: 8 bipolar pathological gamblers were treated with quetiapine (800 7135 mg/d) and reported full remission of gambling behavior after 87 1 weeks (Mannu and Minnai, 2005). Finally, a case report described the usefulness of quetiapine as add-on treatment for the management of BD type I and comorbid ‘behavioral addictions’ (compulsive buying and obligatory physical exercise) (Di Nicola et al., 2010c). Taken together, data from studies on addictive behaviors and OCD support the potential effectiveness of quetiapine as an add-on treatment in BD–GD patients, mainly aimed at improving craving, anxiety and compulsive repetition. Aripiprazole. Aripiprazole acts as a partial agonist at dopamine D2 and 5-HT1A receptors and as an antagonist at the 5-HT2A receptor (Shapiro et al., 2003). It is used in the treatment of BD (manic and mixed episodes) and it has also been found to be effective as augmentation in treatment-resistant OCD (Sayyah et al., 2012). A small, 12-week, open-label study tested the efficacy of aripiprazole in BD patients with polysubstance abuse (alcohol, cocaine, opioids and cannabis) and found that it significantly improved mood symptoms, decreased alcohol and cocaine craving and reduced money spent per week for alcohol (Brown et al., 2005). A pilot study suggested a possible role of this drug in the treatment of alcohol-dependent subjects with ‘dual diagnosis’ (Janiri et al., 2007) and a placebo-controlled trial found that it reduced alcohol consumption and severity of alcohol dependence (Anton et al., 2008). A subsequent RCT comparing aripiprazole to naltrexone in alcohol-dependent subjects reported longer duration of abstinence in the aripiprazole group, while naltrexone had a greater impact on craving (Martinotti et al., 2009). Some authors have reported cases of aripiprazole-induced GD in patients with schizophrenia or schizoaffective disorder (Cohen et al., 2011; Roxanas, 2010). Also, other case reports suggest that gambling may worsen following treatment with aripiprazole in psychotic patients (Smith et al., 2011). These data are preliminary and do not allow us to draw definite conclusions. Though we cannot determine to what extent treatment with aripiprazole may affect gambling behavior, given its partial dopaminergic agonist

activity, evidence available so far suggests aripiprazole might be potentially useful in comorbid BD–GD, especially in patients with relevant obsessive–compulsive features. Risperidone. Risperidone is a DA antagonist with anti-serotonergic, anti-adrenergic and anti-histaminergic properties (Leysen et al., 1994; Schotte et al., 1996) used to treat schizoaffective disorder as well as mixed and manic states. It is approved for maintenance treatment in BD patients. Evidence supports risperidone as an adjunct to SSRIs in treatment-refractory OCD patients (Maher and Theodore, 2012). Interestingly, in an open-label study, refractory OCD patients receiving risperidone augmentation displayed fewer and less severe obsessive–compulsive symptoms, and a greater improvement was observed in patients with comorbid BD (Pfanner et al., 2000). In cocaine-dependent BD and major depressed patients risperidone was safe, well-tolerated and decreased cocaine craving and use (Albanese and Suh, 2006). As previously reported in the section on quetiapine, risperidone decreased drug craving and overall drug use in BD patients with comorbid cocaine or methamphetamine use (Nejtek et al., 2008). To date, no studies have assessed risperidone in GD. Risperidone may be a useful adjunctive treatment in comorbid BD–GD patients with predominant obsessive–compulsive symptoms. However, current available data is insufficient. Risperidone is, in some ways, more similar to typical antipsychotics: on the IGT, patients treated with risperidone performed more like those treated with haloperidol than those treated with other atypical antipsychotics (Wasserman et al., 2012). Since, in a sample of GD patients, haloperidol significantly increased self-reported rewarding effects of gambling (Zack and Poulos, 2007), use of risperidone in GD patients requires caution.

6.2.4. Opioid antagonists The efficacy of opioid antagonists in the treatment of addictive disorders, including GD, has been proposed to involve opioidergic modulation of mesolimbic dopaminergic circuitry. Opioid antagonist administration leads to diminished urges to engage in the addictive behavior and longer periods of abstinence (Grant et al., 2008a), and this is consistent with a mechanism of action involving ventral striatal DA systems. Naltrexone. Naltrexone is a competitive antagonist at μ- and k-opioid receptors, and to a lesser extent at δ-opioid receptors, which are thought to be involved in the rewarding properties of several substances such as opiates, cocaine and alcohol (Ray et al., 2010). It blocks the effect of endogenous endorphins on central opiate receptors and also inhibits DA release in the nucleus accumbens, acting on neuronal pathways involved in reward, pleasure and urge. The inhibition of DA release in the nucleus accumbens, through the disinhibition of GABA input to the DA neurons in the ventral tegmental area, is one of the most consistent reasons for the use of naltrexone in addictive disorders (Ray et al., 2010). Several clinical trials have investigated the use of naltrexone in GD. In an 11-week, double-blind, placebo-controlled study, GD patients were randomly assigned to naltrexone (up to 250 mg/d) or placebo (Kim et al., 2001). Naltrexone demonstrated superiority over placebo: also, patients with moderate or high levels of gambling urges at baseline had a better response to naltrexone than other patients. The same authors subsequently conducted an 18-week, double-blind, placebo-controlled trial (Grant et al., 2008b). Due to their findings from the previous trial, only subjects who reported gambling due to urges or cravings were enrolled. On the primary outcome measure (PG-YBOCS), those on naltrexone had a greater average decrease than those on placebo.

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To date, no studies have examined the use of naltrexone in pathological gamblers with BD. There is, however, some evidence on the efficacy of naltrexone in BD and alcohol dependence comorbidity. In a pilot RCT, naltrexone, compared to placebo, showed trends toward a greater decrease in drinking days, alcohol craving and some liver enzyme levels (Brown et al., 2009). In view of the evidence supporting the use of naltrexone in pathological gamblers as well as its safety and effectiveness in bipolar patients with comorbid alcohol dependence, future studies should test its efficacy as add-on treatment in BD–GD comorbidity. Nalmefene. Nalmefene is a dual-acting opioid system modulator with distinct μ, δ, and k-receptor profile (antagonist activity at the μ and δ opioid receptors and partial agonist activity at the k opioid receptor) (Keating, 2013). It was initially investigated in the treatment of GD in a 16-week, randomized, double-blind, placebocontrolled trial (Grant et al., 2006). Subjects receiving nalmefene 25 mg/d had a statistically significant reduction in severity of GD compared to those on placebo. A subsequent confirmatory study involved a double-blind, placebo-controlled RCT of nalmefene with a single-blind placebo lead-in phase for 1 week (Grant et al., 2010b). A significant difference in mean PG-YBOCS scores between patients receiving 40 mg/d nalmefene and the placebo group was observed. To date, there is no evidence on the use of nalmefene in BD patients. Even so, besides its usefulness in GD, nalmefene is approved in the EU for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level (van den Brink et al., 2013; Keating, 2013). Hence, future studies investigating nalmefene adjunct in BD–GD comorbidity are warranted.

6.2.5. Glutamatergic drugs Manipulation of glutamatergic neurotransmission is a relatively new but promising path for the treatment of substance and behavioral addictions, including GD (Olive et al., 2012; Pettorruso et al., 2014a). Furthermore, accruing evidence suggests that the glutamatergic system is central to the neurobiology of mood disorders, and glutamatergic agents have been demonstrated to be effective in the treatment of mood disorders (Machado-Vieira et al., 2012). Indeed, some current antidepressants and mood stabilizers modulate different components of the glutamatergic system. Previously discussed anticonvulsants, such as topiramate, lamotrigine, gabapentin and pregabalin, inhibit presynaptic voltagegated Na þ and Ca2 þ channels, thereby inhibiting the release of glutamate. Topiramate also acts as an antagonist at AMPA receptors, glutamate receptor subtypes that mediate relapse-like behaviors and are involved in the neuroadaptive changes produced by drugs of abuse (Gass and Olive, 2008). Converging data from the fields of BD and GD allow us to hypothesize that targeting the glutamatergic system may be a valuable therapeutic option in the treatment of comorbid patients. N-acetylcysteine (NAC), an amino acid that seems to restore extracellular Glu concentration in the nucleus accumbens, effectively reduced gambling urges and behavior (lower scores on the PG-YBOCS) in a small clinical trial (Grant et al., 2007), recently confirmed in an RCT (Grant et al., 2014). It has also been studied, in an open-label setting, for the treatment of moderate bipolar depression, and it was found to significantly reduce depression scores and yield improvements in functioning and quality of life (Berk et al., 2011). Results from a small RCT confirm the effectiveness of NAC as adjunctive treatment for bipolar depression (Magalhães et al., 2011). These results suggest that NAC may be useful as add-on treatment in patients with comorbid BD–GD, especially during depressive episodes. Memantine, a noncompetitive antagonist at the NMDA receptor, is currently approved for moderate to severe Alzheimer’s disease,

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but it is being studied in a variety of psychiatric disorders as well. Recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant BD patients (Sani et al., 2012; Koukopulos et al., 2012). In GD patients, memantine decreased PG-YBOCS scores and time spent gambling. It also improved neurocognitive function related to cognitive flexibility (Grant et al., 2010a). In light of these results, memantine could be of use in BD–GD comorbidity. Amantadine, an antiglutamatergic drug with additional actions on dopaminergic neurotransmission, has been tested and found to be effective in GD patients with Parkinson's disease (Thomas et al., 2010). Also, a recent case study reports that amantadine may be a valid treatment option in patients with GD alone (Pettorruso et al., 2012). In BD, add-on treatment with amantadine has been found to improve cognitive impairment and manic symptoms (Ohlmeier et al., 2007, 2008). However, it has also been shown to increase the risk of manic switches (Sodré et al., 2010). A cautious use of amantadine is, therefore, recommended in pathological gamblers with comorbid BD. Acamprosate (calcium acetylhomotaurinate) is a taurine derivative and a nonspecific GABA agonist that promotes a balance between excitatory and inhibitory neurotransmitters (glutamate and GABA). It binds specifically to GABAB receptors, and appears to block glutamate receptors and inhibit hyperactive glutamatergic signaling (Tomek et al., 2013). It is approved by the FDA for alcohol dependence and is well-tolerated in patients with co-occurring BD (Tolliver et al., 2012), in whom no worsening of depressive or manic symptoms was observed. Contrasting results have been reported on its use in GD treatment. In an open-label trial, acamprosate significantly improved PG-YBOCS, G-SAS and CGI scores as well as gambling behavior (Black et al., 2011), while another study failed to confirm its efficacy (Dannon et al., 2011). Future studies are warranted to replicate these findings and thus clarify the possible role of acamprosate in BD–GD comorbidity.

6.2.6. Antidepressants Numerous studies have investigated the efficacy of antidepressants (mostly SSRIs) in treating pathological gamblers; on the whole, these drugs seem to be well-tolerated and effective (Black et al., 2007b; Leung and Cottler, 2009). Also, in most studies the efficacy of SSRIs was independent of underlying depressive or anxious comorbidity. This supports the notion that in a subset of GD patients impulsivity is driven by serotonergic dysregulation. In this subtype, the use of an SSRI might normalize the serotonergic dysfunction and improve patients’ clinical condition (Dell’Osso and Hollander, 2005). However, in pathological gamblers with comorbid bipolar spectrum disorders, the administration of antidepressants may worsen and precipitate the overall clinical picture, with the risk of inducing hypomania and mania (Leverich et al., 2006), though this issue is quite controversial (Gijsman et al., 2004). Therefore, in these patients the use of antidepressants is not recommended. A possible exception is bupropion, a DA and norepinephrine reuptake inhibitor. Bupropion is notably associated with low rates of switch to mania or hypomania and its short-term addition to mood-stabilizer therapy does not increase the risk of cycling (Sachs et al., 2007). Available evidence, though not unambiguous, suggests that bupropion may be useful in pathological gamblers, even if preliminary data about its misuse potential deserve further investigation (Hilliard et al., 2013). Black (2004) first reported positive findings in an 8-week, open-label trial involving 10 pathological gamblers treated with bupropion up to 300 mg/d. Subsequently, Black et al. (2007a) conducted a 12-week, double-blind, placebocontrolled trial involving non-depressed GD subjects. The primary outcome measure was the PG-YBOCS, with secondary measures including the G-SAS and CGI. Although significant improvement

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was observed in both groups, no statistical difference was found between bupropion and placebo. Dannon et al. (2005b) compared sustained-release bupropion to naltrexone in a 12-week, blind-rater study. Bupropion was essentially as effective as naltrexone in treating GD, though individuals in the bupropion group typically increased doses to the highest level to obtain results while those taking naltrexone often responded to more moderate doses. On the whole, current data support the use of bupropion in patients with comorbid BD–GD. However, as previously mentioned, mood stabilizers are at least as effective as SSRIs in treating pathological gamblers without comorbid conditions (Dannon et al., 2005a); therefore, they are all the more preferable to bupropion in gamblers with comorbid BD. Possibly, bupropion, in combination with a mood-stabilizer therapy, may be of particular use in comorbid BD–GD patients when gambling is primarily linked to the emergence of depressive symptomatology.

7. Conclusions BD and GD often co-occur, and this has important clinical implications. BD–GD patients experience a more severe course of illness and poorer treatment outcome, due to a range of clinical and psychosocial factors that collectively impede remission and recovery. Even so, few studies reported to date have specifically explored the profile of comorbid BD–GD patients, and data on BD– GD comorbidity treatment is very limited (Table 2). This frequent comorbidity is not surprising if one focuses on some of the psychopathological core features of GD: impulsivity, urges, anxiety and affective instability, pleasure seeking, and decreased judgment. Along with these, pathological gamblers also present with a compulsive drive to gamble as well as addictive features such as craving and withdrawal symptoms (Olsen, 2011; George et al., 2012). Based on the conceptualization of GD as a non-substancerelated disorder and on existing evidence, we propose an algorithm with a dimensional approach for the treatment of BD–GD comorbidity (Fig. 1). These are suggestions that may contribute to the complex clinical management of bipolar patients with comorbid GD. We set certain clinical dimensions as targets for treatment development. The primary aim of pharmacological treatment strategies should be to target affective instability and ensure mood regulation. Residual symptom domains common to this comorbid condition that cause distress or dysfunction and residual addictive symptoms should also be adequately treated. Further randomized controlled trials with long-term follow-up are required to evaluate the efficacy of these treatment strategies in large samples of patients with BD–GD comorbidity. Also, attempts should be made to identify other shared clinical and psychopathological domains that are amenable to treatment. Future studies should also investigate the differential treatment effects and the potential utility of combined pharmacological and psychosocial treatment strategies (Vieta et al., 2009). Additional measures (genetic, neuroimaging, neuropsychological features) might help to identify factors that can be used to select appropriate treatments on an individual basis and may also better define brain mechanisms predicting and mediating the effectiveness of specific treatments.

Role of funding source No pharmaceutical and industry support was employed in this study.

Conflict of interest All authors declare that there are no conflicts of interest.

Acknowledgments We wish to thank Dr. Daniela Tedeschi and Dr. Filippo Ruggeri for editing support.

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