RESEARCH ARTICLE
Neurobiological and Clinical Variables Associated with Alcohol Abuse in Bulimia Nervosa Francisco J. Vaz-Leal1,2*, María I. Ramos-Fuentes1, Laura Rodríguez-Santos1, Isabel S. Flores-Mateos2, Andrés Franco-Zambrano2, Luis Rojo-Moreno3,4 & Luis Beato-Fernández5,6 1
Faculty of Medicine, University of Extremadura, Badajoz, Spain Mental Health and Eating Disorders Unit (University Hospital Network), Badajoz, Spain 3 Faculty of Medicine, University of Valencia, Valencia, Spain 4 Eating Disorders Unit, Hospital la Fe, Valencia, Spain 5 Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain 6 Eating Disorders Unit, General Hospital of Ciudad Real, Ciudad Real, Spain 2
Abstract The study was aimed at analysing the reciprocal relationships of several clinical and neurobiological items in order to predict alcohol misuse in patients with bulimia nervosa (BN). Seventy BN patients and 70 healthy controls were assessed for depression, impulsivity, borderline personality traits and self-defeating behaviours using specific scales; serum cortisol and 24-hour urinary excretion of serotonin and 5-hydroxiindolacetic acid were also assessed. The study confirmed the implications of these clinical factors for alcohol misuse in BN patients, but the results suggested that depressive symptoms and hypercortisolism could lie behind these relationships. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association. Keywords bulimia nervosa; alcohol; hypothalamic–pituitary–adrenal (HPA) axis; cortisol; serotonin *Correspondence Francisco J. Vaz-Leal, Facultad de Medicina, Área de Psiquiatría, Avda. de Elvas, s/n, 06071 Badajoz, Spain. Telephone: +34 924 218 002; Fax: +34 924 218 005. Email: [email protected] Published online 12 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/erv.2352
Introduction Substance use is a serious health problem, which is frequently detected in patients with bulimia nervosa (BN; Bulik, Sullivan, Carter, & Joyce, 1997; Corcos, et al., 2001; Courbasson, Smith, & Cleland, 2005; Stock, Goldberg, Corbett, & Katzman, 2002). Several models have been proposed to explain the association between substance-related disorders (SRD) and BN, including the consideration of BN itself as an addictive disorder (Davis & Claridge, 1998; Krahn, 1991). Other models have attempted to analyse the relationship between SRD and BN from a causal point of view, identifying both SRD as a risk factor for the development of BN and BN as a risk factor for the development of SRD (Strasser, Pike, & Walsh, 1992; Wiseman, et al., 1999). The most widely accepted theory is that SRD and BN can be viewed as comorbid conditions, which co-occur at a rate greater than expected (Wilson, 2002). Several studies reporting on alcohol misuse or abuse describe higher rates in BN patients than in controls (Bulik, et al., 1997, 2004; Dansky, Brewerton, & Kilpatrick, 2000; Hatsukami, Mitchell, Eckert, & Pyle, 1986; Kaltiala-Heino, Rissanen, Rimpela, & Rantanen, 2003; Schuckit, et al., 1996; Suzuki, Takeda, & Matsushita, 1995; Trace, et al., 2013), and in most of the cases, alcohol use seems to produce more negative consequences in patients with BN than in normal subjects (Dunn, Larimer, &
Neighbors, 2002; Fernández-Aranda, et al., 2009; Shisslak, Schnaps, & Crago, 1988), being frequently associated with impulsive behaviours (Bulik, et al., 2004; Kaltiala-Heino, et al., 2003; Nagata, Kawarada, Ohshima, Iketani, & Kiriike, 2002). Several studies have reported on the association between substance use and mood disorder, impulsivity and self-defeating behaviours, not only in patients with BN but also in non-clinical samples (Anderson, Simmons, Martens, Ferrier, & Sheehy, 2006; Kaltiala-Heino, et al., 2003; Krahn, Kurth, Demitrack, & Drewnowski, 1992; Suzuki, et al., 1995), although patients with co-morbid BN and SRD seem to be more prone to have a history of self-damaging and self-defeating behaviours (Dohm, et al., 2002; Nagata, Kawarada, Kiriike, & Iketani, 2000; Welch & Fairburn, 1996; Wiederman & Pryor, 1996a, 1996b), especially those identified as having a multi-impulsive form of BN (Fichter, Quadflieg, & Rief, 1994; Lacey, 1993). Some underlying shared factors could contribute to the development of BN and alcohol use disorder: genetic factors and family vulnerability (Chandy, Harris, Blum, & Resnick, 1994; Forcano, et al., 2009; Kaye, et al., 1996; Lilenfeld, et al., 1997; Nisoli, et al., 2007; Trace, et al., 2013), mood disorders (Bulik, et al., 1997; Hatsukami, et al., 1986; Stice, Presnell, & Bearman, 2001), anxiety disorders (Bulik, et al., 2004), impulsivity (Corcos, et al., 2001; Dawe & Loxton, 2004; Kaltiala-Heino, et al., 2003) and other factors associated with character, temperament, personality traits and
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personality disorders (Bulik, et al., 1997, 2004; Koepp, Schildbach, Schmager, & Rohner, 1993; Lilenfeld, et al., 1997; Nagata, Oshima, Wada, Yamada, & Kiriike, 2003). Recent research has led us to isolate a set of neurobiological and psychopathological variables, which seem to be able to differentiate patients with BN from healthy controls (Vaz-Leal, Rodríguez-Santos, García-Herráiz, & Ramos Fuentes, 2009; 2011; Vaz-Leal, Rodríguez-Santos, Ramos-Fuentes, CardosoMoreno, & Fernández-Sánchez, 2009). The psychopathological parameters are depressive symptoms, impulsivity, borderline personality traits and self-defeating behaviours (all of them increased in BN patients), and the neurobiological ones are 24-hour excretion of serotonin (5HT) and capability to suppress cortisol after dexamethasone administration (the two of them decreased in BN patients). As research in the field of addictions has revealed not only the co-morbid presence in patients with alcohol use/misuse of the four isolated clinical variables (Kazemi, Flowers, Shou, Levine, & Van Horn, 2014; MacLean, & French, 2014; Picci, et al., 2012; Pringuey, et al., 2014) but also the serotonergic system (Seneviratne et al., 2013; Watanabe et al., 2014; Wrzosek et al., 2012) and the pattern of cortisol liberation that can affect alcohol consumption (Badrick, et al., 2008; Junghanns, Horbach, Ehrenthal, Blank, & Backhaus, 2007; Stalder et al., 2010), the first objective of our study was to analyse the specificity of depressive symptoms, impulsivity, borderline personality symptoms and self-defeating behaviours in order to predict alcohol heavy use (AHU) in a sample of patients with BN. The second objective was to test the hypothesis that 5HT and hypothalamus–pituitary–adrenal (HPA) axis activity will be associated with AHU, considering that BN patients will have a specific profile, different from that found in healthy individuals. According to the results from literature and from our previous research, and as a general hypothesis, we supposed that the presence of these clinical and neurobiological items will increase the likelihood of AHU in patients with BN but not in normal controls.
Materials and methods Design The research was designed as an unmatched case–control crosssectional study: patients fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for BN versus individuals without past and/or current eating disorder. In order to calculate the sample size, the estimate of the prevalence of AHU in patients with BN was set at 47%, according to the data from Bulik, et al. (1997), which were in accordance with other studies on prevalence of alcohol misuse in BN of similar design (Dansky et al., 2000; Mann et al., 2014). As we had detected a prevalence of AHU of 19.9% in the non-clinical participants in a previous pilot study, the risk difference to be detected was established in 27 percentage points. The significance level was then fixed at 5% and power at 90%. Using these values, the size of the sample was estimated in 69 cases in each group. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The 186
University Institutional Review Board approved all research procedures. All group members signed Institutional Review Board (IRB) approved informed consents. Participants Seventy female outpatients seeking treatment at a University Hospital Eating Disorders Unit were selected for the study. The Eating Disorders Unit is a reference centre, giving attention to a population of 650 000 inhabitants. A mean of 300 new patients, usually with severe forms of eating disorder, is attended each year. We selected initially 75 consecutive patients with BN, but in order to homogenize the clinical sample, we decided to exclude from the study two patients who had the non-purging subtype of BN, as well as three patients who had incomplete records. All patients were Caucasian. They were free of psychotropic medication and drugs (excluding benzodiazepines, ordinary analgesics and tobacco) for at least 15 days before the moment of the assessment. Selection criteria for patients were as follows: (i) to meet at the time of assessment the diagnostic criteria for BN, according to the DSM-IV-TR; (ii) to have a Body Mass Index (BMI) over 18.5 kg/m2 and below 35.0 kg/m2; and (iii) to consent to enter the study. Table 1 shows the descriptive demographic characteristics of the sample (patients and controls). The mean BMI of the selected patients was 22.9 kg/m2 (SD 3.4; range 19.0–34.0). The mean of binging at the time of the assessment was 1 per day (ranging from 2 to 35 per week). The mean for vomiting was 1 per day (ranging from 2 to 21 per week). Seventy healthy female Caucasian participants were recruited as controls, from a group of students who attended a course on eating disorders at our Medical School. Initially, a group of 100 potential candidates was recruited. A trained psychologist discussed the study with them and answered questions. They were not paid for their participation. Participants who met the screening criteria (absence of past/current eating disorder) were approached to participate in the first part of the study, involving a face-to-face interview. They completed clinical questionnaires and were interviewed. Past and/or current eating disorder was excluded using the same semi-structured interview used with patients (see succeeding text, under ‘Psychopathological Items’ section). Then, the 70 participants without past/current eating disorder who had lower scores in the two clinical scales for eating psychopathology (see succeeding text, under ‘Psychopathological Items’ section) were selected. Differences in age between patients and controls did not exist [difference of means (95% confidence interval (IC)) = 3 ( 0.6 to 1.2); p-value = 0.50]. The nutritional/clinical status was assessed, and biological samples were obtained from this group, following the procedures described in the succeeding text for the patients. Assessment Nutritional status The nutritional status was assessed using anthropometric and bioelectrical methods. All the measurements were taken immediately after the diagnostic interview. The assessment process
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Table 1 Demographic characteristics of the sample
Age, mean (SD) Gender N (%) Female Education N (%) Primary Secondary University Home location N (%) Urban Suburban Race/ethnicity N (%) Caucasian Marital status N (%) Single, living with family Single, living alone Married/living with spouse or partner Divorced Other Work status N (%) Studying Studying and working Working Unemployed Disabled
Patients (N = 70)
Controls (N = 70)
21.5 (1.8)
21.2 (1.8)
70 (100)
70 (100)
2 (2.8) 8 (11.4) 60 (85.7)
0 (0) 0 (0) 70 (100)
65 (92.9) 5 (7.1)
68 (97.1) 2 (2.9)
70 (100)
70 (100)
45 (64.3) 14 (20.0) 11 (15.7) — —
33 (47.1) 19 (27.1) 16 (22.9) 1 (1.4) 1 (1.4)
54 (77.1) 8 (11.4) 6 (8.6) 2 (2.8) —
55 (78.6) 15 (21.4) — — —
included measuring of height and weight using a balance scale, determination of middle arm point circumference with an anthropometric tape measure, skinfold thickness assessment by means of a lipocaliper and body impedance analysis using a tetrapolar impedance plethysmograph. Skinfold and arm circumference measurements were introduced into specific equations in order to calculate other supplementary nutritional parameters (Gurney & Jelliffe, 1973; Heymsfield, McMannus, Smith, Stevens, & Nixon, 1982; Jelliffe, 1996). High correlations between BMI and the other nutritional parameters were found for the whole sample (the Pearson correlations were: 0.89, p = 0.001 for body fat content; 0.62, p = 0.001 for fat-free mass; and 0.75, p = 0.001 for percent fat content). We considered, therefore, that BMI would be a reliable indicator of the nutritional status of our sample, and we decided to use it for statistical analysis in order to simplify the process. Psychopathological items For the assessment of psychopathological items, specific clinical tools were used. Alcohol use was assessed by using the Section A of the Maudsley Addiction Profile (Marsden, et al., 1998), adapted for exploring both current and past use of substances. As several preventive programmes, as the Preventive Activities and Health Promotion Program (PAAPS) recommendations, Spanish Family and Community Medicine, semFYC) or guidelines of the National Institute on Alcohol Abuse and Alcoholism set in 170 g of alcohol per week the risk level for women, the participants were considered heavy alcohol users if they drank more than 170 g of alcohol per week, that is 17 standard drink units, adapted to the Spanish standard (Gual, Contel, Segura, Ribas, & Colom, 2001). The Bulimic Investigatory Test Edinburgh (Henderson & Freeman,
1987) and the 40-item version of the Eating Attitudes Test (Garner & Garfinkel, 1979) were used for assessing the severity of the eating symptoms, using in both cases the total score. The severity of the depressive symptoms was assessed by using the Beck Depression Inventory (BDI; Beck, 1978). For the assessment of impulsivity, the Impulsive Behavior Scale-Revised (IBS-R) was used (Rosotto, Yager, & Rorty, 1998). The IBS-R is a 25-item self-report questionnaire, which quantifies impulsivity according to the frequency of a variety of behaviours through the course of life, providing a global score. The Spanish version of the scale (Peñas-Lledó, Vaz, Ramos, & Waller, 2002) was used. Self-defeating personality traits were investigated by using the self-defeating personality subscale of the Millon Multiaxial Clinical Inventory (MCMI-2; Millon, 1987). These personality traits include the avoidance or undermining of pleasurable experiences, as well as the tendency to maintain relationships in which the subject suffers, preventing others from helping him or her. Finally, borderline personality features were assessed by using a semi-structured interview, the Diagnostic Interview for Borderline Patients-Revised (DIB-R; Zanarini, Frankenburg, & Vujanovic, 2002). All scales had validated Spanish versions. Laboratory tests Blood samples and 24-hour urine samples from each subject were obtained in 48 hours following the clinical assessment. All the participants were free of psychotropic medication at the moment of assessment. The blood samples were taken at 8:00 AM, after 12 hours of fasting. The venepuncture was preceded by a rest of 30 minutes. The level of serum cortisol was determined in this sample of blood using competitive immunoenzymatic assay methods. The same day, the participants took 1 mg of dexamethasone at 11:00 PM, and a second sample of blood was obtained next morning at 8:00 AM. Serum cortisol level was investigated again using this second sample of blood. As can be seen, we followed the usual procedure of the dexamethasone suppression test, overnight version. The dexamethasone suppression test is used to diagnose Cushing’s syndrome and also to investigate the functioning of the HPA axis in depression, alcoholism and other mental disorders. In the way we applied the test, a cortisol level after dexamethasone administration below 5 μg/dl (suppression) is considered an indicator of normal functioning of the HPA axis, whereas cortisol levels above this value (non-suppression) suggest abnormal functioning of the HPA axis. In our sample, as only five participants in the patients group (7% of the sample) and three participants in the control group (4%) were ‘non-suppressors’, we generated a continuous variable, which we called ‘capability to suppress cortisol’, using the following formula: [(cortisol after dexamethasone/basal cortisol) × 100]. Urinary 24-hour excretion of serotonin (5HT) and its main metabolite, 5-hydroxiindolacetic acid (5HIAA), were assessed using column chromatographic methods. The urinary levels of 5HT and 5HIAA were corrected for urinary creatinine concentration. Statistical procedures First, a chi-squared test (odds ratio and 95% IC) was used to analyse the risk of heavy drinking in the sample. Second, an independent samples t test was used to compare the following groups for the isolated variables: (i) patients versus
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controls; (ii) patients with AHU versus patients without AHU; and (iii) controls with AHU versus controls without AHU. Third, three stepwise logistic regression tests (Wald, forward selection) were performed to analyse the combined effect of the variables. In all cases, the independent variables were BMI, the scores in the clinical scales (IBS, BDI, MCMI-2 self-defeating subscale and DIB-R), the 24-hour excretion rate of 5HT and 5HIAA, the levels of morning serum cortisol before and after dexamethasone and the percentage of suppression of cortisol after dexamethasone administration. In the first analysis, the dependent variable was the initial allocation group (patients versus controls). In the second one, the patients with AHU and the patients without AHU were compared. In the third one, the study was replicated on controls (controls with AHU versus controls without AHU). Bonferroni correction was introduced to control type I error. The significance level was fixed at 0.004. Finally, structural equation model methods were used to confirm the validity of the obtained model.
Results The prevalence of AHU in our sample, according to the data from the Maudsley Addiction Profile, was 33% (23/70) in the group of patients and 23% (16/70) in the control group (odds ratio 1.7; 95% IC 0.8 to 3.5; p = 0.13). The lifetime prevalence of AHU was 60% (42/70) in patients and 40% (28/70) in controls (odds ratio 2.3; 95% IC 1.1 to 4.4; p = 0.014). Table 2 shows the differences between patients and controls regarding the clinical and biological variables considered in the study. It can be seen that significant differences between groups were found for BMI, severity of eating psychopathology (Eating Attitudes Test-40 items and Bulimic Investigatory Test Edinburgh scores), depressive symptoms severity (BDI score), borderline
personality traits (DIB-R total score), self-defeating personality traits (MCMI-2) and impulsivity (IBS). In all cases, the patients had higher scores. They also had higher levels of morning cortisol and had a lower capability to suppress cortisol after dexamethasone administration. Table 3 shows the differences between the four isolated groups (patients with AHU, patients without AHU, controls with AHU and controls without AHU) in clinical scores, 5HT and 5HIAA excretion, and cortisol before and after dexamethasone administration. From this table, it can be observed that the patients had more severe depressive symptoms than the controls. In addition, the BN patients with AHU had more severe borderline personality traits, more impulsive behaviours and a lower capability to suppress serum cortisol after dexamethasone administration. The BN patients without AHU had higher morning cortisol levels. As we have already said, the combined effect of the variables was investigated in the sample (patients versus controls) using stepwise logistic regression. Two variables remained significant in the model after excluding non-significant predictors one by one: the severity of the depressive symptoms, reflected in the BDI score (adjusted odds ratio = 1.13; 95% IC = 1.08 to 1.19; p = 0.001), and basal morning cortisol level (adjusted odds ratio = 1.16; 95% IC = 1.08 to 1.25; p = 0.001). When the same study was applied to patients and controls separately, using in both cases AHU as dependent variable, the capability to suppress cortisol was negatively associated with AHU in the group of BN patients (adjusted odds ratio = 0.90; 95% IC = 0.83 to 0.97; p = 0.005). In fact, the percentage of suppression was 86% for BN patients with AHU and 94% for BN patients without AHU. In the control group, no variable appeared as significant. Finally, we used structural equation methods to test the obtained model. Figure 1 shows the model that provided higher goodness of fit for patients [chi-square = 1.235; degrees of freedom = 2; probability level (p) = 0.539; Tucker–Lewis Index = 1.020; root
Table 2 Differences between patients and controls Mean (SD)
Clinical variables BMI EAT-40 score BITE score BDI score DIB-R total score Self-defeating subscale score IBS score Neurobiological parameters Serotonin (μg/24 hours) 5HIAA (mg/24 hours) Morning cortisol (μg/dl) Morning cortisol after dexamethasone (μg/dl) Supression of cortisol (%)
Patients (N = 70)
Controls (N = 70)
Difference of means (95% IC)
p-value
22.9 (3.4) 45.3 (19.6) 22.4 (6.4) 21.0 (12.0) 2.8 (2.3) 35.3 (13.9) 43.1 (14.9)
21.0 (1.6) 13.4 (6.5) 3.7 (2.2) 11.0 (6.1) 1.6 (0.9) 24.3 (16.2) 31.5 (19.2)
1.9 (0.5 to 3.3) 31.9 (27.0 to 36.7) 18.7 (17.1 to 20.3) 10.0 (6.8 to 13.1) 1.2 (0.6 to 1.8) 10.9 (5.9 to 16.0) 11.6 (5.9 to 17.4)
0.001 0.001 0.001 0.001 0.001 0.001 0.001
109.3 (62.4) 4.04 (3.07) 21.4 (9.4) 1.5 (1.5) 91.5 (9.5)
125.2 (56.1) 4.62 (2.89) 15.6 (4.4) 1.3 (1.4) 95.1 (3.1)
15.8 ( 35.6 to 4.0) 0.6 ( 1.6 to 0.4) 5.7 (3.3 to 8.2) 0.3 ( 0.3 to 0.7) 3.6 ( 6.0 to 1.2)
0.12 0.25 0.001 0.4 0.003
Abbreviations: BMI, Body Mass Index; EAT-40, Eating Attitudes Test-40 items; BITE, Bulimic Investigatory Test Edinburgh; BDI, Beck Depression Inventory; DIB-R, Diagnostic Interview for Borderline Patients-Revised; IBS, Impulsive Behaviours Scale; 5HIAA, 5-hydroxyindolacetic acid.
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Table 3 Differences between patients and controls, grouped for alcohol heavy use (AHU) Patients
Clinical items BDI score* DIB-R total score† MCMI-2 self-defeating subscale score‡ IBS score† Neurobiological parameters Serotonin (μg/24 hours) 5HIAA (mg/24 hours) Morning cortisol (μg/dl)§ Morning cortisol after dexamethasone (μg/dl) Supression of cortisol (%)†
Controls
AHU (N = 23)
No AHU (N = 47)
AHU (N = 16)
No AHU (N = 54)
22.7 (13.7) 3.7 (2.4) 36.4 (18.4) 49.5 (17.1)
20.2 (11.1) 2.4 (2.1) 34.7 (11.3) 39.9 (12.8)
10.4 1.6 25.4 29.4
(5.6) (1.0) (16.8) (16.5)
11.2 (6.2) 1.6 (0.9) 24.0 (16.1) 32.1 (20.0)
118.7 (70.0) 4.12 (3.13) 20.1 (8.0) 1.7 (1.9) 85.8 (13.5)
104.8 (58.6) 4.00 (3.07) 22.0 (10.0) 1.4 (1.3) 94.3 (4.8)
121.9 4.67 15.4 1.5 94.9
(38.2) (3.19) (4.5) (1.7) (4.7)
126.1 (60.7) 4.35 (2.18) 15.7 (4.4) 1.2 (1.3) 95.2 (5.5)
DBI, Beck Depression Inventory; DIB-R, Diagnostic Interview for Borderline Patients-Revised; MCMI-2, Millon Multiaxial Clinical Inventory II; IBS, Impulsive Behaviours Scale; 5HIAA, 5-hydroxyindolacetic acid. Significant differences after post-hoc analysis (Schefè): *Patients versus controls. † BN+/AHU+ versus the other groups. ‡ BN+ versus BN–/AHU–. § BN+/AHU– versus BN–.
Index = –0.116; RMSEA = 0.230; 95% IC for RMSEA 0.097 to 0.388].
Discussion
Figure 1 Confirmation of the model using structural equations model
mean square error of approximation (RMSEA)
Neurobiological and Clinical Variables Associated with Alcohol Abuse in Bulimia Nervosa Francisco J. Vaz-Leal1,2*, María I. Ramos-Fuentes1, Laura Rodríguez-Santos1, Isabel S. Flores-Mateos2, Andrés Franco-Zambrano2, Luis Rojo-Moreno3,4 & Luis Beato-Fernández5,6 1
Faculty of Medicine, University of Extremadura, Badajoz, Spain Mental Health and Eating Disorders Unit (University Hospital Network), Badajoz, Spain 3 Faculty of Medicine, University of Valencia, Valencia, Spain 4 Eating Disorders Unit, Hospital la Fe, Valencia, Spain 5 Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain 6 Eating Disorders Unit, General Hospital of Ciudad Real, Ciudad Real, Spain 2
Abstract The study was aimed at analysing the reciprocal relationships of several clinical and neurobiological items in order to predict alcohol misuse in patients with bulimia nervosa (BN). Seventy BN patients and 70 healthy controls were assessed for depression, impulsivity, borderline personality traits and self-defeating behaviours using specific scales; serum cortisol and 24-hour urinary excretion of serotonin and 5-hydroxiindolacetic acid were also assessed. The study confirmed the implications of these clinical factors for alcohol misuse in BN patients, but the results suggested that depressive symptoms and hypercortisolism could lie behind these relationships. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association. Keywords bulimia nervosa; alcohol; hypothalamic–pituitary–adrenal (HPA) axis; cortisol; serotonin *Correspondence Francisco J. Vaz-Leal, Facultad de Medicina, Área de Psiquiatría, Avda. de Elvas, s/n, 06071 Badajoz, Spain. Telephone: +34 924 218 002; Fax: +34 924 218 005. Email: [email protected] Published online 12 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/erv.2352
Introduction Substance use is a serious health problem, which is frequently detected in patients with bulimia nervosa (BN; Bulik, Sullivan, Carter, & Joyce, 1997; Corcos, et al., 2001; Courbasson, Smith, & Cleland, 2005; Stock, Goldberg, Corbett, & Katzman, 2002). Several models have been proposed to explain the association between substance-related disorders (SRD) and BN, including the consideration of BN itself as an addictive disorder (Davis & Claridge, 1998; Krahn, 1991). Other models have attempted to analyse the relationship between SRD and BN from a causal point of view, identifying both SRD as a risk factor for the development of BN and BN as a risk factor for the development of SRD (Strasser, Pike, & Walsh, 1992; Wiseman, et al., 1999). The most widely accepted theory is that SRD and BN can be viewed as comorbid conditions, which co-occur at a rate greater than expected (Wilson, 2002). Several studies reporting on alcohol misuse or abuse describe higher rates in BN patients than in controls (Bulik, et al., 1997, 2004; Dansky, Brewerton, & Kilpatrick, 2000; Hatsukami, Mitchell, Eckert, & Pyle, 1986; Kaltiala-Heino, Rissanen, Rimpela, & Rantanen, 2003; Schuckit, et al., 1996; Suzuki, Takeda, & Matsushita, 1995; Trace, et al., 2013), and in most of the cases, alcohol use seems to produce more negative consequences in patients with BN than in normal subjects (Dunn, Larimer, &
Neighbors, 2002; Fernández-Aranda, et al., 2009; Shisslak, Schnaps, & Crago, 1988), being frequently associated with impulsive behaviours (Bulik, et al., 2004; Kaltiala-Heino, et al., 2003; Nagata, Kawarada, Ohshima, Iketani, & Kiriike, 2002). Several studies have reported on the association between substance use and mood disorder, impulsivity and self-defeating behaviours, not only in patients with BN but also in non-clinical samples (Anderson, Simmons, Martens, Ferrier, & Sheehy, 2006; Kaltiala-Heino, et al., 2003; Krahn, Kurth, Demitrack, & Drewnowski, 1992; Suzuki, et al., 1995), although patients with co-morbid BN and SRD seem to be more prone to have a history of self-damaging and self-defeating behaviours (Dohm, et al., 2002; Nagata, Kawarada, Kiriike, & Iketani, 2000; Welch & Fairburn, 1996; Wiederman & Pryor, 1996a, 1996b), especially those identified as having a multi-impulsive form of BN (Fichter, Quadflieg, & Rief, 1994; Lacey, 1993). Some underlying shared factors could contribute to the development of BN and alcohol use disorder: genetic factors and family vulnerability (Chandy, Harris, Blum, & Resnick, 1994; Forcano, et al., 2009; Kaye, et al., 1996; Lilenfeld, et al., 1997; Nisoli, et al., 2007; Trace, et al., 2013), mood disorders (Bulik, et al., 1997; Hatsukami, et al., 1986; Stice, Presnell, & Bearman, 2001), anxiety disorders (Bulik, et al., 2004), impulsivity (Corcos, et al., 2001; Dawe & Loxton, 2004; Kaltiala-Heino, et al., 2003) and other factors associated with character, temperament, personality traits and
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personality disorders (Bulik, et al., 1997, 2004; Koepp, Schildbach, Schmager, & Rohner, 1993; Lilenfeld, et al., 1997; Nagata, Oshima, Wada, Yamada, & Kiriike, 2003). Recent research has led us to isolate a set of neurobiological and psychopathological variables, which seem to be able to differentiate patients with BN from healthy controls (Vaz-Leal, Rodríguez-Santos, García-Herráiz, & Ramos Fuentes, 2009; 2011; Vaz-Leal, Rodríguez-Santos, Ramos-Fuentes, CardosoMoreno, & Fernández-Sánchez, 2009). The psychopathological parameters are depressive symptoms, impulsivity, borderline personality traits and self-defeating behaviours (all of them increased in BN patients), and the neurobiological ones are 24-hour excretion of serotonin (5HT) and capability to suppress cortisol after dexamethasone administration (the two of them decreased in BN patients). As research in the field of addictions has revealed not only the co-morbid presence in patients with alcohol use/misuse of the four isolated clinical variables (Kazemi, Flowers, Shou, Levine, & Van Horn, 2014; MacLean, & French, 2014; Picci, et al., 2012; Pringuey, et al., 2014) but also the serotonergic system (Seneviratne et al., 2013; Watanabe et al., 2014; Wrzosek et al., 2012) and the pattern of cortisol liberation that can affect alcohol consumption (Badrick, et al., 2008; Junghanns, Horbach, Ehrenthal, Blank, & Backhaus, 2007; Stalder et al., 2010), the first objective of our study was to analyse the specificity of depressive symptoms, impulsivity, borderline personality symptoms and self-defeating behaviours in order to predict alcohol heavy use (AHU) in a sample of patients with BN. The second objective was to test the hypothesis that 5HT and hypothalamus–pituitary–adrenal (HPA) axis activity will be associated with AHU, considering that BN patients will have a specific profile, different from that found in healthy individuals. According to the results from literature and from our previous research, and as a general hypothesis, we supposed that the presence of these clinical and neurobiological items will increase the likelihood of AHU in patients with BN but not in normal controls.
Materials and methods Design The research was designed as an unmatched case–control crosssectional study: patients fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for BN versus individuals without past and/or current eating disorder. In order to calculate the sample size, the estimate of the prevalence of AHU in patients with BN was set at 47%, according to the data from Bulik, et al. (1997), which were in accordance with other studies on prevalence of alcohol misuse in BN of similar design (Dansky et al., 2000; Mann et al., 2014). As we had detected a prevalence of AHU of 19.9% in the non-clinical participants in a previous pilot study, the risk difference to be detected was established in 27 percentage points. The significance level was then fixed at 5% and power at 90%. Using these values, the size of the sample was estimated in 69 cases in each group. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The 186
University Institutional Review Board approved all research procedures. All group members signed Institutional Review Board (IRB) approved informed consents. Participants Seventy female outpatients seeking treatment at a University Hospital Eating Disorders Unit were selected for the study. The Eating Disorders Unit is a reference centre, giving attention to a population of 650 000 inhabitants. A mean of 300 new patients, usually with severe forms of eating disorder, is attended each year. We selected initially 75 consecutive patients with BN, but in order to homogenize the clinical sample, we decided to exclude from the study two patients who had the non-purging subtype of BN, as well as three patients who had incomplete records. All patients were Caucasian. They were free of psychotropic medication and drugs (excluding benzodiazepines, ordinary analgesics and tobacco) for at least 15 days before the moment of the assessment. Selection criteria for patients were as follows: (i) to meet at the time of assessment the diagnostic criteria for BN, according to the DSM-IV-TR; (ii) to have a Body Mass Index (BMI) over 18.5 kg/m2 and below 35.0 kg/m2; and (iii) to consent to enter the study. Table 1 shows the descriptive demographic characteristics of the sample (patients and controls). The mean BMI of the selected patients was 22.9 kg/m2 (SD 3.4; range 19.0–34.0). The mean of binging at the time of the assessment was 1 per day (ranging from 2 to 35 per week). The mean for vomiting was 1 per day (ranging from 2 to 21 per week). Seventy healthy female Caucasian participants were recruited as controls, from a group of students who attended a course on eating disorders at our Medical School. Initially, a group of 100 potential candidates was recruited. A trained psychologist discussed the study with them and answered questions. They were not paid for their participation. Participants who met the screening criteria (absence of past/current eating disorder) were approached to participate in the first part of the study, involving a face-to-face interview. They completed clinical questionnaires and were interviewed. Past and/or current eating disorder was excluded using the same semi-structured interview used with patients (see succeeding text, under ‘Psychopathological Items’ section). Then, the 70 participants without past/current eating disorder who had lower scores in the two clinical scales for eating psychopathology (see succeeding text, under ‘Psychopathological Items’ section) were selected. Differences in age between patients and controls did not exist [difference of means (95% confidence interval (IC)) = 3 ( 0.6 to 1.2); p-value = 0.50]. The nutritional/clinical status was assessed, and biological samples were obtained from this group, following the procedures described in the succeeding text for the patients. Assessment Nutritional status The nutritional status was assessed using anthropometric and bioelectrical methods. All the measurements were taken immediately after the diagnostic interview. The assessment process
Eur. Eat. Disorders Rev. 23 (2015) 185–192 © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.
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Table 1 Demographic characteristics of the sample
Age, mean (SD) Gender N (%) Female Education N (%) Primary Secondary University Home location N (%) Urban Suburban Race/ethnicity N (%) Caucasian Marital status N (%) Single, living with family Single, living alone Married/living with spouse or partner Divorced Other Work status N (%) Studying Studying and working Working Unemployed Disabled
Patients (N = 70)
Controls (N = 70)
21.5 (1.8)
21.2 (1.8)
70 (100)
70 (100)
2 (2.8) 8 (11.4) 60 (85.7)
0 (0) 0 (0) 70 (100)
65 (92.9) 5 (7.1)
68 (97.1) 2 (2.9)
70 (100)
70 (100)
45 (64.3) 14 (20.0) 11 (15.7) — —
33 (47.1) 19 (27.1) 16 (22.9) 1 (1.4) 1 (1.4)
54 (77.1) 8 (11.4) 6 (8.6) 2 (2.8) —
55 (78.6) 15 (21.4) — — —
included measuring of height and weight using a balance scale, determination of middle arm point circumference with an anthropometric tape measure, skinfold thickness assessment by means of a lipocaliper and body impedance analysis using a tetrapolar impedance plethysmograph. Skinfold and arm circumference measurements were introduced into specific equations in order to calculate other supplementary nutritional parameters (Gurney & Jelliffe, 1973; Heymsfield, McMannus, Smith, Stevens, & Nixon, 1982; Jelliffe, 1996). High correlations between BMI and the other nutritional parameters were found for the whole sample (the Pearson correlations were: 0.89, p = 0.001 for body fat content; 0.62, p = 0.001 for fat-free mass; and 0.75, p = 0.001 for percent fat content). We considered, therefore, that BMI would be a reliable indicator of the nutritional status of our sample, and we decided to use it for statistical analysis in order to simplify the process. Psychopathological items For the assessment of psychopathological items, specific clinical tools were used. Alcohol use was assessed by using the Section A of the Maudsley Addiction Profile (Marsden, et al., 1998), adapted for exploring both current and past use of substances. As several preventive programmes, as the Preventive Activities and Health Promotion Program (PAAPS) recommendations, Spanish Family and Community Medicine, semFYC) or guidelines of the National Institute on Alcohol Abuse and Alcoholism set in 170 g of alcohol per week the risk level for women, the participants were considered heavy alcohol users if they drank more than 170 g of alcohol per week, that is 17 standard drink units, adapted to the Spanish standard (Gual, Contel, Segura, Ribas, & Colom, 2001). The Bulimic Investigatory Test Edinburgh (Henderson & Freeman,
1987) and the 40-item version of the Eating Attitudes Test (Garner & Garfinkel, 1979) were used for assessing the severity of the eating symptoms, using in both cases the total score. The severity of the depressive symptoms was assessed by using the Beck Depression Inventory (BDI; Beck, 1978). For the assessment of impulsivity, the Impulsive Behavior Scale-Revised (IBS-R) was used (Rosotto, Yager, & Rorty, 1998). The IBS-R is a 25-item self-report questionnaire, which quantifies impulsivity according to the frequency of a variety of behaviours through the course of life, providing a global score. The Spanish version of the scale (Peñas-Lledó, Vaz, Ramos, & Waller, 2002) was used. Self-defeating personality traits were investigated by using the self-defeating personality subscale of the Millon Multiaxial Clinical Inventory (MCMI-2; Millon, 1987). These personality traits include the avoidance or undermining of pleasurable experiences, as well as the tendency to maintain relationships in which the subject suffers, preventing others from helping him or her. Finally, borderline personality features were assessed by using a semi-structured interview, the Diagnostic Interview for Borderline Patients-Revised (DIB-R; Zanarini, Frankenburg, & Vujanovic, 2002). All scales had validated Spanish versions. Laboratory tests Blood samples and 24-hour urine samples from each subject were obtained in 48 hours following the clinical assessment. All the participants were free of psychotropic medication at the moment of assessment. The blood samples were taken at 8:00 AM, after 12 hours of fasting. The venepuncture was preceded by a rest of 30 minutes. The level of serum cortisol was determined in this sample of blood using competitive immunoenzymatic assay methods. The same day, the participants took 1 mg of dexamethasone at 11:00 PM, and a second sample of blood was obtained next morning at 8:00 AM. Serum cortisol level was investigated again using this second sample of blood. As can be seen, we followed the usual procedure of the dexamethasone suppression test, overnight version. The dexamethasone suppression test is used to diagnose Cushing’s syndrome and also to investigate the functioning of the HPA axis in depression, alcoholism and other mental disorders. In the way we applied the test, a cortisol level after dexamethasone administration below 5 μg/dl (suppression) is considered an indicator of normal functioning of the HPA axis, whereas cortisol levels above this value (non-suppression) suggest abnormal functioning of the HPA axis. In our sample, as only five participants in the patients group (7% of the sample) and three participants in the control group (4%) were ‘non-suppressors’, we generated a continuous variable, which we called ‘capability to suppress cortisol’, using the following formula: [(cortisol after dexamethasone/basal cortisol) × 100]. Urinary 24-hour excretion of serotonin (5HT) and its main metabolite, 5-hydroxiindolacetic acid (5HIAA), were assessed using column chromatographic methods. The urinary levels of 5HT and 5HIAA were corrected for urinary creatinine concentration. Statistical procedures First, a chi-squared test (odds ratio and 95% IC) was used to analyse the risk of heavy drinking in the sample. Second, an independent samples t test was used to compare the following groups for the isolated variables: (i) patients versus
Eur. Eat. Disorders Rev. 23 (2015) 185–192 © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.
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controls; (ii) patients with AHU versus patients without AHU; and (iii) controls with AHU versus controls without AHU. Third, three stepwise logistic regression tests (Wald, forward selection) were performed to analyse the combined effect of the variables. In all cases, the independent variables were BMI, the scores in the clinical scales (IBS, BDI, MCMI-2 self-defeating subscale and DIB-R), the 24-hour excretion rate of 5HT and 5HIAA, the levels of morning serum cortisol before and after dexamethasone and the percentage of suppression of cortisol after dexamethasone administration. In the first analysis, the dependent variable was the initial allocation group (patients versus controls). In the second one, the patients with AHU and the patients without AHU were compared. In the third one, the study was replicated on controls (controls with AHU versus controls without AHU). Bonferroni correction was introduced to control type I error. The significance level was fixed at 0.004. Finally, structural equation model methods were used to confirm the validity of the obtained model.
Results The prevalence of AHU in our sample, according to the data from the Maudsley Addiction Profile, was 33% (23/70) in the group of patients and 23% (16/70) in the control group (odds ratio 1.7; 95% IC 0.8 to 3.5; p = 0.13). The lifetime prevalence of AHU was 60% (42/70) in patients and 40% (28/70) in controls (odds ratio 2.3; 95% IC 1.1 to 4.4; p = 0.014). Table 2 shows the differences between patients and controls regarding the clinical and biological variables considered in the study. It can be seen that significant differences between groups were found for BMI, severity of eating psychopathology (Eating Attitudes Test-40 items and Bulimic Investigatory Test Edinburgh scores), depressive symptoms severity (BDI score), borderline
personality traits (DIB-R total score), self-defeating personality traits (MCMI-2) and impulsivity (IBS). In all cases, the patients had higher scores. They also had higher levels of morning cortisol and had a lower capability to suppress cortisol after dexamethasone administration. Table 3 shows the differences between the four isolated groups (patients with AHU, patients without AHU, controls with AHU and controls without AHU) in clinical scores, 5HT and 5HIAA excretion, and cortisol before and after dexamethasone administration. From this table, it can be observed that the patients had more severe depressive symptoms than the controls. In addition, the BN patients with AHU had more severe borderline personality traits, more impulsive behaviours and a lower capability to suppress serum cortisol after dexamethasone administration. The BN patients without AHU had higher morning cortisol levels. As we have already said, the combined effect of the variables was investigated in the sample (patients versus controls) using stepwise logistic regression. Two variables remained significant in the model after excluding non-significant predictors one by one: the severity of the depressive symptoms, reflected in the BDI score (adjusted odds ratio = 1.13; 95% IC = 1.08 to 1.19; p = 0.001), and basal morning cortisol level (adjusted odds ratio = 1.16; 95% IC = 1.08 to 1.25; p = 0.001). When the same study was applied to patients and controls separately, using in both cases AHU as dependent variable, the capability to suppress cortisol was negatively associated with AHU in the group of BN patients (adjusted odds ratio = 0.90; 95% IC = 0.83 to 0.97; p = 0.005). In fact, the percentage of suppression was 86% for BN patients with AHU and 94% for BN patients without AHU. In the control group, no variable appeared as significant. Finally, we used structural equation methods to test the obtained model. Figure 1 shows the model that provided higher goodness of fit for patients [chi-square = 1.235; degrees of freedom = 2; probability level (p) = 0.539; Tucker–Lewis Index = 1.020; root
Table 2 Differences between patients and controls Mean (SD)
Clinical variables BMI EAT-40 score BITE score BDI score DIB-R total score Self-defeating subscale score IBS score Neurobiological parameters Serotonin (μg/24 hours) 5HIAA (mg/24 hours) Morning cortisol (μg/dl) Morning cortisol after dexamethasone (μg/dl) Supression of cortisol (%)
Patients (N = 70)
Controls (N = 70)
Difference of means (95% IC)
p-value
22.9 (3.4) 45.3 (19.6) 22.4 (6.4) 21.0 (12.0) 2.8 (2.3) 35.3 (13.9) 43.1 (14.9)
21.0 (1.6) 13.4 (6.5) 3.7 (2.2) 11.0 (6.1) 1.6 (0.9) 24.3 (16.2) 31.5 (19.2)
1.9 (0.5 to 3.3) 31.9 (27.0 to 36.7) 18.7 (17.1 to 20.3) 10.0 (6.8 to 13.1) 1.2 (0.6 to 1.8) 10.9 (5.9 to 16.0) 11.6 (5.9 to 17.4)
0.001 0.001 0.001 0.001 0.001 0.001 0.001
109.3 (62.4) 4.04 (3.07) 21.4 (9.4) 1.5 (1.5) 91.5 (9.5)
125.2 (56.1) 4.62 (2.89) 15.6 (4.4) 1.3 (1.4) 95.1 (3.1)
15.8 ( 35.6 to 4.0) 0.6 ( 1.6 to 0.4) 5.7 (3.3 to 8.2) 0.3 ( 0.3 to 0.7) 3.6 ( 6.0 to 1.2)
0.12 0.25 0.001 0.4 0.003
Abbreviations: BMI, Body Mass Index; EAT-40, Eating Attitudes Test-40 items; BITE, Bulimic Investigatory Test Edinburgh; BDI, Beck Depression Inventory; DIB-R, Diagnostic Interview for Borderline Patients-Revised; IBS, Impulsive Behaviours Scale; 5HIAA, 5-hydroxyindolacetic acid.
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Table 3 Differences between patients and controls, grouped for alcohol heavy use (AHU) Patients
Clinical items BDI score* DIB-R total score† MCMI-2 self-defeating subscale score‡ IBS score† Neurobiological parameters Serotonin (μg/24 hours) 5HIAA (mg/24 hours) Morning cortisol (μg/dl)§ Morning cortisol after dexamethasone (μg/dl) Supression of cortisol (%)†
Controls
AHU (N = 23)
No AHU (N = 47)
AHU (N = 16)
No AHU (N = 54)
22.7 (13.7) 3.7 (2.4) 36.4 (18.4) 49.5 (17.1)
20.2 (11.1) 2.4 (2.1) 34.7 (11.3) 39.9 (12.8)
10.4 1.6 25.4 29.4
(5.6) (1.0) (16.8) (16.5)
11.2 (6.2) 1.6 (0.9) 24.0 (16.1) 32.1 (20.0)
118.7 (70.0) 4.12 (3.13) 20.1 (8.0) 1.7 (1.9) 85.8 (13.5)
104.8 (58.6) 4.00 (3.07) 22.0 (10.0) 1.4 (1.3) 94.3 (4.8)
121.9 4.67 15.4 1.5 94.9
(38.2) (3.19) (4.5) (1.7) (4.7)
126.1 (60.7) 4.35 (2.18) 15.7 (4.4) 1.2 (1.3) 95.2 (5.5)
DBI, Beck Depression Inventory; DIB-R, Diagnostic Interview for Borderline Patients-Revised; MCMI-2, Millon Multiaxial Clinical Inventory II; IBS, Impulsive Behaviours Scale; 5HIAA, 5-hydroxyindolacetic acid. Significant differences after post-hoc analysis (Schefè): *Patients versus controls. † BN+/AHU+ versus the other groups. ‡ BN+ versus BN–/AHU–. § BN+/AHU– versus BN–.
Index = –0.116; RMSEA = 0.230; 95% IC for RMSEA 0.097 to 0.388].
Discussion
Figure 1 Confirmation of the model using structural equations model
mean square error of approximation (RMSEA)
