Eating Behaviors 16 (2015) 84–87
Contents lists available at ScienceDirect
Eating Behaviors
Disulfiram for binge eating disorder: An open trail Anna Maria Giulia Farci a, Simona Piras a, Magnolia Murgia a, Alessandra Chessa a, Angelo Restivo b, Gian Luigi Gessa c,d, Roberta Agabio d,⁎ a
Clinical Nutrition Center, Department of Medical Sciences “M. Aresu” University of Cagliari, Italy Colorectal Surgery Center, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Cagliari, Italy d Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy b c
a r t i c l e
i n f o
Article history: Received 12 May 2014 Received in revised form 15 September 2014 Accepted 24 October 2014 Available online 3 November 2014 Keywords: Binge eating disorder Disulfiramside side effects
a b s t r a c t Objective: To evaluate the efficacy and safety of disulfiram for treatment of binge eating disorder. Method: Two hundred and fifty milligrams per day of disulfiram was administered to 12 patients affected by binge eating disorder for 16 weeks; the number of binge eating episodes per week and the number of participants who reported side effects were evaluated. Results: Nine participants (75.0%) completed the trial, while the other 3 (25.0%) discontinued prematurely. Disulfiram significantly decreased the mean frequency of binge eating episodes per week from 7.9 ± 1.2 to 0.9 ± 0.6 (p b .001). All patients (100.0%) reduced the frequency of binge eating episodes, and 7 participants (58.3%) achieved remission of binge eating. Eleven participants (91.7%) reported side effects [drowsiness (N = 9), headache (N = 7), dysgeusia (N = 3), tachycardia (N = 3), dizziness (N = 2), and nausea (N = 2)]. Discussion: While disulfiram reduced the frequency of binge eating episodes, side effects were observed in the majority of participants. Longer-term placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability. © 2014 Elsevier Ltd. All rights reserved.
1. Introductions Binge eating disorder (BED) is a distressing, relative common mental illness characterized by recurrent episodes of binge eating without inappropriate behaviors aimed at losing weight (Treasure, Claudino, & Zucker, 2010). BED patients frequently suffer from other comorbid physical and/or mental illnesses, such as obesity, mood, and anxiety disorders (Grilo, White, Barnes, & Masheb, 2013; Lin et al., 2013). No medication is yet approved for treatment of BED (Mitchell, Roerig, & Steffen, 2013). Certain BED features resemble those of Alcohol Use Disorder (AUD) such as the urge to consume food and the lack of control parallel the strong urge to consume alcohol (craving) and the lack of control characteristic of AUD patients (Pelchat, 2009). These disorders also share similar neural substrates (Volkow, Wang, & Baler, 2011). The consumption Abbreviations: ALDH, aldehyde dehydrogenase; AUD, alcohol use disorder; BED, binge eating disorder; BES, Binge Eating Scale; BMI, body mass index; BW, body weight; CGI-S, Clinical Global Impression Severity Scale; DA, dopamine; DβH, dopamine β-hydroxylase; ITT, intention to treat; NA, noradrenaline; SF-12, questionnaire used to measure the quality of life; VAS, Visual Analogue Scale; ZUNG, Zung Self-Rating Depression Scale. ⁎ Corresponding author at: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, S.S. 554, km. 4.500, I-09042 Monserrato (CA), Italy. Tel.: +39 070 6754325. E-mail address: [email protected] (R. Agabio).
http://dx.doi.org/10.1016/j.eatbeh.2014.10.008 1471-0153/© 2014 Elsevier Ltd. All rights reserved.
of food (particularly those rich in sugars and fat), like alcohol consumption, induce rewarding effects, at least in part, through activation of the mesolimbic dopaminergic “reward” system (Koob & Volkow, 2010; Umberg, Shader, Hsu, & Greenblatt, 2012). In vulnerable individuals, the consumption of high quantities of palatable food or alcohol may facilitate the development of BED and AUD, respectively (Umberg et al., 2012). Accordingly, it has been hypothesized that AUD medications may be effective for the treatment of BED, and almost all these drugs have been tested in BED patients, with inconsistent results, except disulfiram, the oldest medication approved for AUD (McElroy, Guerdjikova, Mori, & O'Melia, 2012; Suh, Pettinati, Kampman, & O'Brien, 2006). The therapeutic effect of disulfiram for AUD is mediated by inhibition of aldehyde dehydrogenase (ALDH), the enzyme responsible for converting acetaldehyde to acetate, in alcohol metabolism. ALDH inhibition causes acetaldehyde accumulation after alcohol intake, and a consequent aversive reaction to this toxic intermediate that deters further alcohol use (Skinner, Lahmek, Pham, & Aubin, 2014). According to this mechanism of action, disulfiram should be not of interest for the treatment of BED or for the treatment of other substance use disorder. However disulfiram also inhibits the function of dopamine β-hydroxylase (DβH), the enzyme responsible for converting dopamine (DA) to noradrenaline (NA) in the final step of NA synthesis in noradrenergic neurons (Barth & Malcolm, 2010; Hald & Jacobsen, 1948). DβH inhibition constitutes
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
85
the mechanism proposed to explain the efficacy of disulfiram in the treatment of cocaine use disorder (Barth & Malcolm, 2010; Kosten et al., 2013; Pani et al., 2010). Through the same mechanism of action, disulfiram may reduce the severity of food craving in BED. Accordingly, the present study tested the efficacy and safety of disulfiram in a sample of BED patients.
by assessment of the regularity of scheduled visits and by counting the returned tablets. The percentage of participants who achieved remission of binge eating (defined as no binge eating episodes for 1 month, with no missing observations).
2. Methods
The primary outcomes were the number of binge eating episodes per week and the number of patients who reported side effects. Secondary outcome measures were BW, BMI, CGI-S, VAS, BES, SF-12, and ZUNG scores.
2.1. Study design This was an open study conducted at the University Hospital of Cagliari, Italy. After a screening visit, selected patients received 250 mg/day disulfiram per os, for 16 weeks. During this period, patients were visited once a week for the first 4 weeks, then every 2 weeks for the remaining 10 weeks, and 2 weeks after cessation of disulfiram treatment. The Institutional Review Board at the University of Cagliari approved the study protocol (Authorization no. 7178, December 6, 2012). 2.2. Participant selection criteria Subjects were recruited from patients seeking weight loss treatment at the University Hospital of Cagliari. Patients were eligible if they met DSM-IV-TR criteria for BED (APA, 2000) and had a body mass index (BMI; body weight in kg divided by height in m2) ≥25 kg/m2. Other inclusion criteria were (1) 21 − 65 years of age, (2) residence in a location that allowed the patient to comply with the scheduled visits, and (3) able to understand the aims of the study, agree to participate in the study and abstain from alcohol, and signing the informed consent form. Exclusion criteria were (1) diagnosis of current or past AUD; (2) diagnosis of physical diseases (e.g. heart disease) or psychiatric disorders (e.g. psychotic disorder) that, in the screening physician's opinion, may constitute a danger for participation in the study; (3) ≥1 lifetime suicide attempts; 4) start of any pharmacological treatment with the past 2 months; and (5) use of psychotherapy and/or pharmacotherapy for BED, and/or to lose weight. 2.3. Procedures At the screening evaluation, patients were given a physical examination and BMI calculated. Women of childbearing age were given a urine pregnancy test. Only patients with normal blood chemical and hematological tests and negative pregnancy test were eligible for the first visit. At the first visit, patients underwent psychiatric assessment to investigate the diagnosis of BED, and the presence of mental comorbidity according to DSM-IV-TR criteria (APA, 2000). At each visit, participants underwent psychiatric assessment to investigate the severity of BED symptomatology and the possible appearance of psychotic symptoms due to disulfiram administration. At each visit, the Binge Eating Scale (BES) and the Clinical Global Impression Severity Scale (CGI-S) were administered to assess the severity of binge eating behavior; a 100-mm Visual Analogue Scale (VAS) was used to investigate the severity of food craving; the Zung Self-Rating Depression Scale (ZUNG) was used to assess the severity of depressive symptoms (Zung, 1965); the SF-12 questionnaire was administered to measure quality of life (Ware, Kosinski, & Keller, 1996). A diary was used to self-register the number of binge eating episodes per day. Participants were instructed to monitor and record into the diary the number of binge eating episodes per day, the type of food consumed, and the duration of each episode. Binge eating episodes were defined using DSM-IV-TR criteria. At each visit, the diaries were reviewed with participants, and the mean number of binge eating episodes per week was calculated. The diaries were provided to participants at the screening evaluation, and each of the following visits. Possible side effects were investigated using open-ended questioning. Compliance was evaluated
2.4. Outcome measures
2.5. Statistical analysis Data were analyzed using IBM SPSS Statistics software, Version 21.0. A longitudinal repeated-measures random regression analysis with a term for time as the fixed effect was performed. The analysis assessed the change of each variable measured at each visit during the treatment period (frequency of binge episodes per week, BW, BMI, scores obtained in the CGI-S, VAS, BES, SF-12, and ZUNG). Time was modeled as a continuous variable, with weeks ranging from 0 (baseline) to 16, after beginning treatment with disulfiram. The measure of effect was the estimated change in the outcome at week 16. The data were analyzed by using a mixed effect model with maximum likelihood estimation. First-order autoregressive covariance structure for repeated and random effect was used, as this resulted the best fitting model with the lowest standard error of the estimates. The analysis was intent-to-treat, using available observations on all participants who completed a baseline evaluation. A secondary analysis was an end point analysis of the change from baseline, applying a one-sample t test to the last observation carried forward (LOCF). A two sided p value b .05 was considered significant. 3. Results Of 31 candidates screened, 19 were not enrolled because they (a) did not meet the criteria for BED (N = 6), (b) withdrew consent (N = 7), (c) started a new pharmacotherapy within the past two months (N = 3), or (d) were lost after the screening visit (N = 2). One patient was not recruited because she could not have complied with the scheduled visits. Twelve individuals (11 women) met criteria and received disulfiram (sample used for safety analysis). At baseline, mean age was 44.2 years (SD = 9.5), mean BW was 92.8 kg (SD = 2.9), the mean number of binge eating episodes per week was 7.9 (SD = 1.2, range 14 − 3), and mean age of onset of BED was 24.3 years (SD = 11.8, range 10–40 years). Seven out of these 12 patients (58.3%) were affected by comorbid mood and/or anxiety disorders. The intention to treat (ITT) sample included all participants. Nine participants (75.0%) completed the 16-week trial, while the other 3 (25.0%) discontinued prematurely after a mean of 3.3 (SD = 0.6) weeks in the study (Table 1). Reasons for withdrawal were unknown (lost to follow-up, N = 1), and adverse events (N = 2; headache for 1 participant and drowsiness for the other). The observed mean outcome measures at last post-baseline visit and at week 16 (for the 9 completers) along with the analysis of change in outcome measures are presented in Table 2. Both the longitudinal and end point analyses revealed a statistically significant decrease in mean frequency of binge eating episodes, and a significant improvement in all the other items (Table 2). A high degree of compliance was observed in completing the diaries. At study termination, all patients (100% of recruited patients) reduced the number of binge eating episodes per week, and 7 participants achieved remission of binge eating (58.3%). There was no statistically significant correlation between change in BW and binge episode frequency.
86
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
Table 1 Clinical characteristics and measures by participant. Baseline
1 2 3 4 5 6 7 8 9 10 11 12
At the end of the study
Gender
Age (years)
Duration of BED (years)
Comorbid mood and/or anxiety disorders
Weekly binge eating episode f requency
Body weight (kg)
BMI
Weeks of trial completed
Weekly binge eating episode frequency
Body weight (kg)
BMI
F F F F F M F F F F F F
26 45 41 32 63 48 49 49 50 47 37 43
14 26 5 na 47 12 12 19 36 37 27 3
Yes No Yes No Yes No Yes Yes No No Yes Yes
12 14 11 14 7 7 4 10 3 7 3 3
91.0 105.0 102.0 83.9 94.0 99.0 81.5 93.8 97.2 107.0 87.4 72.5
38.4 40.9 46.4 30.4 35.6 34.4 31.8 33.2 38.9 40.3 35.9 26.0
3 16 16 16 3 16 16 4 16 16 16 16
4 0 0 1 0 0 0 6 0 0 0 0
90.5 101.0 97.0 79.5 94.8 98.5 82.7 93.9 93.6 105.0 88.5 68.1
38.2 39.3 44.1 28.9 35.9 34.4 31.3 33.3 37.4 39.4 36.4 24.4
Eleven participants were women and one was a man. Seven out of 12 participants (58.3%) had comorbid mood and/or anxiety disorders [lifetime mood disorders: participants number 3, 7, 8, 11, and 12; actual mood disorder: participant number 1; actual generalized anxiety disorder: participant number 5]. BED, binge eating disorder; BMI, body mass index (weight in kilograms divided by height in m2); F, female; M, male; na: not available.
2009). The efficacy of disulfiram for the treatment of cocaine use disorder and BED may be due to its ability to increase DA levels, thereby normalizing this “hypodopaminergia” (Devoto, Flore, Saba, Bini, & Gessa, 2013; Devoto, Flore, Saba, Cadeddu, & Gessa, 2012; Kosten et al., 2013). Accordingly, a recent study found that nepicastat, a selective competitive inhibitor of DβH, effectively reduced craving for chocolate and motivation for food consumption sustained by appetite or palatability in rats, suggesting that DβH inhibitors may be effective for the treatment of BED and obesity (Zaru, Maccioni, Colombo, & Gessa, 2013). However, an alteration in the taste of food may have also contributed to the reduction in binge eating as three participants in the current study reported a bitter taste, a frequent side effect of disulfiram referred to as a “garlic-like aftertaste” (Suh et al., 2006). This study has several limitations. First, we cannot eliminate the contribution of a placebo response. A recent study found that, after placebo treatment, approximately 40% of BED patients reduce binge eating episodes, and 30% attain cessation (Blom et al., 2014). The higher number of patients who reduced binge eating episodes and attained cessation in the present study suggest that DβH inhibition may have also contributed to these results. Other limitations of the present study are the small number of participants and the short duration of treatment, motivated by the need to evaluate the safety of disulfiram for BED patients. Finally, in the present study, 7 screened subjects withdrew consent and another 3 were not recruited because mental or physical disorders contraindicated disulfiram administration. Moreover, 2 patients
Eleven participants (91.7%) reported side effects. The most common adverse effects reported were drowsiness (N = 9), headache (N = 7), dysgeusia (N = 3), tachycardia (N = 3), dizziness (N = 2), and nausea (N = 2). One patient decreased the disulfiram dose to 200 mg/day because of excessive somnolence. One patient developed a mild disulfiram-alcohol reaction after consumption of an alcoholic beverage. No participant exhibited significant changes in laboratory test results. 4. Discussion The results of this study show that treatment with disulfiram effectively reduced the frequency of binge eating episodes in a sample of BED patients. This effect may be due, at least in part, to DβH inhibition, the mechanism proposed to explain the efficacy of disulfiram in reducing craving for cocaine and cocaine use in patients affected by cocaine use disorder. Indeed, both drugs of abuse and palatable food increase extracellular DA in the “reward” system, and the subjective perception of pleasure is related to the availability of DA for D2 receptor stimulation within these regions (Mitchell, Roerig, & SteffenK, 2013; Pani et al., 2010). Neuroimaging studies show that both obese individuals and subjects with substance use disorder express fewer D2 receptors than control subjects, suggesting a common “reward deficiency syndrome” (Barry, Clarke, & Petry, 2009). Underexpression of D2 receptors could lead to a propensity for compensatory compulsive engagement in rewarding behaviors, such as drug use and eating (Barry, Clarke, & Petry,
Table 2 Outcome measures before and after 16 weeks of treatment with disulfiram and analysis of change in outcome. Longitudinal analysisa
Mean
BE BW BMI CGI-S VAS BES ZUNG SF-12
Baseline n = 12
Last observation n = 12
7.9 92.8 36.0 4.1 92.1 23.0 37.3 33.3
0.9 91.0 35.2 1.4 62.9 10.6 28.2 38.3
± ± ± ± ± ± ± ±
1.2 2.9 1.6 0.2 4.6 1.7 2.8 2.0
± ± ± ± ± ± ± ±
0.6 2.9 1.5 0.3 10.4 2.8 2.0 1.6
b
Week 16 n = 9 0.1 90.4 35.1 1.1 50.6 7.4 27.9 39.5
± ± ± ± ± ± ± ±
0.1 3.4 1.7 0.1 10.2 2.2 1.9 1.2
c
End point analysisb
Estimate [95% CI]
p value
Estimate [95% CI]
p value
−7.4 [−8.7, −6.2] −2.4 [−3.2, −1.7] −1.0 [−1.4, −0.7] −3.0 [−3.6, −2.4] −35.4 [−48.9, −21.9] −14.9 [−18.7, −11.1] −9.3 [−12.9, −5.7] +5,6 [+2.9, +8.4]
b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001
−7.0 [−9.5, −4.5] −1.8 [−3.3, −0.3] −0.8 [−1.4, −0.2] −2.7 [−3.5, −1.8] −29.2 [−52.8, −5.6] −12.4 [−17.7, −7.1] −9.1 [−14.1, −4.2] +5.1 [+2.3, +7.8]
b.001 .02 .01 b.001 .02 b.001 .002 .002
BE, number of episodes of binge eating per week; BW, body weight (in kilograms); BES, Binge Eating Scale score [a 16-item scale used to assess the severity of binge eating behavior with a total score varying from 0 to 46; (non-binging b17; moderate binging: 18 − 26; severe binging: ≥27)]; BMI, body mass index (weight in kilograms divided by height in m2, normal value b 25); CGI-S: Clinical Global Impression-S, rating scale for clinical global impression of severity of binge eating disorder (BED), with a total score ranging from 1 (no BED) to 7 (the most severe BED); SF-12, score achieved in a 12-item questionnaire used to measure the quality of life [total score varies from 12 to 47 (12 = the worst quality of life; 47 = the best quality of life)]; VAS, score achieved in a Visual Analogue Scale of food craving (0 = no craving and 100 mm = the worst craving)]; ZUNG, score achieved in a 20-item scale used to assess the severity of depressive symptoms [total score varies from 20 to 80; scores N50 are indicative of significant depression)]. a Only those outcomes assessed at each study visit were included into the longitudinal analyses. b last observation end point was defined using last observation carried forward. c Week 16 end point was available for only those participants that completed the study.
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
discontinued the study, 1 participant reduced the dose, and 1 participant developed a mild disulfiram-alcohol reaction. These data suggest that the use of disulfiram in the treatment of BED patients may be limited by side effects or by the risk of exacerbation of psychotic disorders in subjects already suffering by these disorders. In conclusion, disulfiram was found to be effective in reducing the frequency of binge eating episodes however it also induced side effects in the majority of BED patients, suggesting that it may be useful for the treatment of BED but that its use may be limited by side effects. Longerterm placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability. Role of funding sources Disulfiram and pregnancy tests were supplied by AFOM Dipendenze srl and Confarma srl, respectively. AFOM Dipendenze srl and Confarma srl had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. Contributors Drs. Gessa, Farci, and Agabio designed the study and wrote the protocol. Drs. Farci, Agabio, Piras, Murgia, and Mrs. Chessa assessed patients as per study protocol. Dr. Restivo conducted the statistical analysis. All authors contributed to and have approved the final manuscript. Conflict of interest All the authors declare that they have no conflicts of interest. Acknowledgements The authors express sincere gratitude to Drs. Ilaria Cerina, Olga Curreli, Silvia Mercuro, Romina Naitana, and Elisa Tronci for their contribution to the conduction of the study, and Mr. David Cushley for language editing of the manuscript.
References American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association (Text Revision (DSM-IV-TR)). Barry, D., Clarke, M., & Petry, N.M. (2009). Obesity and its relationship to addictions: Is overeating a form of addictive behavior? American Journal of Addictions, 18, 439–451, http://dx.doi.org/10.3109/10550490903205579. Barth, K.S., & Malcolm, R.J. (2010). Disulfiram: An old therapeutic with new applications. CNS & Neurological Disorders Drug Targets, 9, 5–12, http://dx.doi.org/10.2174/ 187152710790966678. Blom, T.J., Mingione, C.J., Guerdjikova, A.I., Keck, P.E., Jr., Welge, J.A., & McElroy, S.L. (2014). Placebo response in binge eating disorder: A pooled analysis of 10 clinical trials from one research group. European Eating Disorders Review, 22, 140–146, http://dx.doi.org/ 10.1002/erv.2277. Devoto, P., Flore, G., Saba, P., Bini, V., & Gessa, G.L. (2013, Jan 7). The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates
87
psychostimulant-induced dopamine release in the prefrontal cortex. Addiction Biology, http://dx.doi.org/10.1111/adb.12026. Devoto, P., Flore, G., Saba, P., Cadeddu, R., & Gessa, G.L. (2012). Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex. Psychopharmacology, 219, 1153–1164, http://dx.doi.org/10.1007/s00213-011-2447-5. Grilo, C.M., White, M.A., Barnes, R.D., & Masheb, R.M. (2013). Psychiatric disorder co-morbidity and correlates in an ethnically diverse sample of obese patients with binge eating disorder in primary care settings. Comprehensive Psychiatry, 54, 209–216, http://dx.doi.org/10.1016/j.comppsych.2012.07.012. Hald, J., & Jacobsen, E. (1948). A drug sensitizing the organism to ethyl alcohol. Lancet, 6539, 1001–1004. Koob, G.F., & Volkow, N.D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35, 217–238, http://dx.doi.org/10.1038/npp.2009.110. Kosten, T.R., Wu, G., Huang, W., Harding, M.J., Hamon, S.C., Lappalainen, J., et al. (2013). Pharmacogenetic randomized trial for cocaine abuse: Disulfiram and dopamine β-hydroxylase. Biological Psychiatry, 73, 219–224, http://dx.doi.org/10.1016/j. biopsych.2012.07.011. Lin, H.Y., Huang, C.K., Tai, C.M., Lin, H.Y., Kao, Y.H., Tsai, C.C., et al. (2013, Jan 2). Psychiatric disorders of patients seeking obesity treatment. BMC Psychiatry, 13(1), http://dx.doi. org/10.1186/1471-244X-13-1. McElroy, S.L., Guerdjikova, A.I., Mori, N., & O'Melia, A.M. (2012). Current pharmacotherapy options for bulimia nervosa and binge eating disorder. Expert Opinion on Pharmacotherapy, 13, 2015–2026, http://dx.doi.org/10.1517/14656566.2012. 721781. Mitchell, J.E., Roerig, J., & Steffen, K. (2013). Biological therapies for eating disorders. The International Journal of Eating Disorders, 46, 470–477, http://dx.doi.org/10.1002/eat. 22104. Pani, P.P., Trogu, E., Vacca, R., Amato, L., Vecchi, S., & Davoli, M. (2010). Disulfiram for the treatment of cocaine dependence. The Cochrane Database of Systematic Reviews, 1, CD007024, http://dx.doi.org/10.1002/14651858.CD007024.pub2. Pelchat, M.L. (2009). Food addiction in humans. The Journal of Nutrition, 139, 620–622, http://dx.doi.org/10.3945/jn.108.097816. Skinner, M.D., Lahmek, P., Pham, H., & Aubin, H.J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: A meta-analysis. PLoS One, 9, e87366, http://dx.doi.org/ 10.1371/journal.pone.0087366. eCollection 2014. Suh, J.J., Pettinati, H.M., Kampman, K.M., & O'Brien, C.P. (2006). The status of disulfiram: A half of a century later. Journal of Clinical Psychopharmacology, 26, 290–302. Treasure, J., Claudino, A.M., & Zucker, N. (2010). Eating disorders. Lancet, 375, 583–593, http://dx.doi.org/10.1016/S0140-6736(09)61748-7. Umberg, E.N., Shader, R.I., Hsu, L.K., & Greenblatt, D.J. (2012). From disordered eating to addiction: The “food drug” in bulimia nervosa. Journal of Clinical Psychopharmacology, 32, 376–389, http://dx.doi.org/10.1097/JCP.0b013e318252464f. Volkow, N.D., Wang, G.J., & Baler, R.D. (2011). Reward, dopamine and the control of food intake: Implications for obesity. Trends in Cognitive Sciences, 15, 37–46, http://dx.doi. org/10.1016/j.tics.2010.11.001. Ware, J., Jr., Kosinski, M., & Keller, S.D. (1996). A 12-Item Short-Form Health Survey: Construction of scales and preliminary tests of reliability and validity. Medical Care, 34, 220–233. Zaru, A., Maccioni, P., Colombo, G., & Gessa, G.L. (2013). The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats. The British Journal of Nutrition, 110, 1524–1533, http://dx. doi.org/10.1017/S0007114513000743. Zung, W.W. (1965). A self-rating depression scale. Archives of General Psychiatry, 12, 63–70.
Contents lists available at ScienceDirect
Eating Behaviors
Disulfiram for binge eating disorder: An open trail Anna Maria Giulia Farci a, Simona Piras a, Magnolia Murgia a, Alessandra Chessa a, Angelo Restivo b, Gian Luigi Gessa c,d, Roberta Agabio d,⁎ a
Clinical Nutrition Center, Department of Medical Sciences “M. Aresu” University of Cagliari, Italy Colorectal Surgery Center, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Cagliari, Italy d Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy b c
a r t i c l e
i n f o
Article history: Received 12 May 2014 Received in revised form 15 September 2014 Accepted 24 October 2014 Available online 3 November 2014 Keywords: Binge eating disorder Disulfiramside side effects
a b s t r a c t Objective: To evaluate the efficacy and safety of disulfiram for treatment of binge eating disorder. Method: Two hundred and fifty milligrams per day of disulfiram was administered to 12 patients affected by binge eating disorder for 16 weeks; the number of binge eating episodes per week and the number of participants who reported side effects were evaluated. Results: Nine participants (75.0%) completed the trial, while the other 3 (25.0%) discontinued prematurely. Disulfiram significantly decreased the mean frequency of binge eating episodes per week from 7.9 ± 1.2 to 0.9 ± 0.6 (p b .001). All patients (100.0%) reduced the frequency of binge eating episodes, and 7 participants (58.3%) achieved remission of binge eating. Eleven participants (91.7%) reported side effects [drowsiness (N = 9), headache (N = 7), dysgeusia (N = 3), tachycardia (N = 3), dizziness (N = 2), and nausea (N = 2)]. Discussion: While disulfiram reduced the frequency of binge eating episodes, side effects were observed in the majority of participants. Longer-term placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability. © 2014 Elsevier Ltd. All rights reserved.
1. Introductions Binge eating disorder (BED) is a distressing, relative common mental illness characterized by recurrent episodes of binge eating without inappropriate behaviors aimed at losing weight (Treasure, Claudino, & Zucker, 2010). BED patients frequently suffer from other comorbid physical and/or mental illnesses, such as obesity, mood, and anxiety disorders (Grilo, White, Barnes, & Masheb, 2013; Lin et al., 2013). No medication is yet approved for treatment of BED (Mitchell, Roerig, & Steffen, 2013). Certain BED features resemble those of Alcohol Use Disorder (AUD) such as the urge to consume food and the lack of control parallel the strong urge to consume alcohol (craving) and the lack of control characteristic of AUD patients (Pelchat, 2009). These disorders also share similar neural substrates (Volkow, Wang, & Baler, 2011). The consumption Abbreviations: ALDH, aldehyde dehydrogenase; AUD, alcohol use disorder; BED, binge eating disorder; BES, Binge Eating Scale; BMI, body mass index; BW, body weight; CGI-S, Clinical Global Impression Severity Scale; DA, dopamine; DβH, dopamine β-hydroxylase; ITT, intention to treat; NA, noradrenaline; SF-12, questionnaire used to measure the quality of life; VAS, Visual Analogue Scale; ZUNG, Zung Self-Rating Depression Scale. ⁎ Corresponding author at: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, S.S. 554, km. 4.500, I-09042 Monserrato (CA), Italy. Tel.: +39 070 6754325. E-mail address: [email protected] (R. Agabio).
http://dx.doi.org/10.1016/j.eatbeh.2014.10.008 1471-0153/© 2014 Elsevier Ltd. All rights reserved.
of food (particularly those rich in sugars and fat), like alcohol consumption, induce rewarding effects, at least in part, through activation of the mesolimbic dopaminergic “reward” system (Koob & Volkow, 2010; Umberg, Shader, Hsu, & Greenblatt, 2012). In vulnerable individuals, the consumption of high quantities of palatable food or alcohol may facilitate the development of BED and AUD, respectively (Umberg et al., 2012). Accordingly, it has been hypothesized that AUD medications may be effective for the treatment of BED, and almost all these drugs have been tested in BED patients, with inconsistent results, except disulfiram, the oldest medication approved for AUD (McElroy, Guerdjikova, Mori, & O'Melia, 2012; Suh, Pettinati, Kampman, & O'Brien, 2006). The therapeutic effect of disulfiram for AUD is mediated by inhibition of aldehyde dehydrogenase (ALDH), the enzyme responsible for converting acetaldehyde to acetate, in alcohol metabolism. ALDH inhibition causes acetaldehyde accumulation after alcohol intake, and a consequent aversive reaction to this toxic intermediate that deters further alcohol use (Skinner, Lahmek, Pham, & Aubin, 2014). According to this mechanism of action, disulfiram should be not of interest for the treatment of BED or for the treatment of other substance use disorder. However disulfiram also inhibits the function of dopamine β-hydroxylase (DβH), the enzyme responsible for converting dopamine (DA) to noradrenaline (NA) in the final step of NA synthesis in noradrenergic neurons (Barth & Malcolm, 2010; Hald & Jacobsen, 1948). DβH inhibition constitutes
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
85
the mechanism proposed to explain the efficacy of disulfiram in the treatment of cocaine use disorder (Barth & Malcolm, 2010; Kosten et al., 2013; Pani et al., 2010). Through the same mechanism of action, disulfiram may reduce the severity of food craving in BED. Accordingly, the present study tested the efficacy and safety of disulfiram in a sample of BED patients.
by assessment of the regularity of scheduled visits and by counting the returned tablets. The percentage of participants who achieved remission of binge eating (defined as no binge eating episodes for 1 month, with no missing observations).
2. Methods
The primary outcomes were the number of binge eating episodes per week and the number of patients who reported side effects. Secondary outcome measures were BW, BMI, CGI-S, VAS, BES, SF-12, and ZUNG scores.
2.1. Study design This was an open study conducted at the University Hospital of Cagliari, Italy. After a screening visit, selected patients received 250 mg/day disulfiram per os, for 16 weeks. During this period, patients were visited once a week for the first 4 weeks, then every 2 weeks for the remaining 10 weeks, and 2 weeks after cessation of disulfiram treatment. The Institutional Review Board at the University of Cagliari approved the study protocol (Authorization no. 7178, December 6, 2012). 2.2. Participant selection criteria Subjects were recruited from patients seeking weight loss treatment at the University Hospital of Cagliari. Patients were eligible if they met DSM-IV-TR criteria for BED (APA, 2000) and had a body mass index (BMI; body weight in kg divided by height in m2) ≥25 kg/m2. Other inclusion criteria were (1) 21 − 65 years of age, (2) residence in a location that allowed the patient to comply with the scheduled visits, and (3) able to understand the aims of the study, agree to participate in the study and abstain from alcohol, and signing the informed consent form. Exclusion criteria were (1) diagnosis of current or past AUD; (2) diagnosis of physical diseases (e.g. heart disease) or psychiatric disorders (e.g. psychotic disorder) that, in the screening physician's opinion, may constitute a danger for participation in the study; (3) ≥1 lifetime suicide attempts; 4) start of any pharmacological treatment with the past 2 months; and (5) use of psychotherapy and/or pharmacotherapy for BED, and/or to lose weight. 2.3. Procedures At the screening evaluation, patients were given a physical examination and BMI calculated. Women of childbearing age were given a urine pregnancy test. Only patients with normal blood chemical and hematological tests and negative pregnancy test were eligible for the first visit. At the first visit, patients underwent psychiatric assessment to investigate the diagnosis of BED, and the presence of mental comorbidity according to DSM-IV-TR criteria (APA, 2000). At each visit, participants underwent psychiatric assessment to investigate the severity of BED symptomatology and the possible appearance of psychotic symptoms due to disulfiram administration. At each visit, the Binge Eating Scale (BES) and the Clinical Global Impression Severity Scale (CGI-S) were administered to assess the severity of binge eating behavior; a 100-mm Visual Analogue Scale (VAS) was used to investigate the severity of food craving; the Zung Self-Rating Depression Scale (ZUNG) was used to assess the severity of depressive symptoms (Zung, 1965); the SF-12 questionnaire was administered to measure quality of life (Ware, Kosinski, & Keller, 1996). A diary was used to self-register the number of binge eating episodes per day. Participants were instructed to monitor and record into the diary the number of binge eating episodes per day, the type of food consumed, and the duration of each episode. Binge eating episodes were defined using DSM-IV-TR criteria. At each visit, the diaries were reviewed with participants, and the mean number of binge eating episodes per week was calculated. The diaries were provided to participants at the screening evaluation, and each of the following visits. Possible side effects were investigated using open-ended questioning. Compliance was evaluated
2.4. Outcome measures
2.5. Statistical analysis Data were analyzed using IBM SPSS Statistics software, Version 21.0. A longitudinal repeated-measures random regression analysis with a term for time as the fixed effect was performed. The analysis assessed the change of each variable measured at each visit during the treatment period (frequency of binge episodes per week, BW, BMI, scores obtained in the CGI-S, VAS, BES, SF-12, and ZUNG). Time was modeled as a continuous variable, with weeks ranging from 0 (baseline) to 16, after beginning treatment with disulfiram. The measure of effect was the estimated change in the outcome at week 16. The data were analyzed by using a mixed effect model with maximum likelihood estimation. First-order autoregressive covariance structure for repeated and random effect was used, as this resulted the best fitting model with the lowest standard error of the estimates. The analysis was intent-to-treat, using available observations on all participants who completed a baseline evaluation. A secondary analysis was an end point analysis of the change from baseline, applying a one-sample t test to the last observation carried forward (LOCF). A two sided p value b .05 was considered significant. 3. Results Of 31 candidates screened, 19 were not enrolled because they (a) did not meet the criteria for BED (N = 6), (b) withdrew consent (N = 7), (c) started a new pharmacotherapy within the past two months (N = 3), or (d) were lost after the screening visit (N = 2). One patient was not recruited because she could not have complied with the scheduled visits. Twelve individuals (11 women) met criteria and received disulfiram (sample used for safety analysis). At baseline, mean age was 44.2 years (SD = 9.5), mean BW was 92.8 kg (SD = 2.9), the mean number of binge eating episodes per week was 7.9 (SD = 1.2, range 14 − 3), and mean age of onset of BED was 24.3 years (SD = 11.8, range 10–40 years). Seven out of these 12 patients (58.3%) were affected by comorbid mood and/or anxiety disorders. The intention to treat (ITT) sample included all participants. Nine participants (75.0%) completed the 16-week trial, while the other 3 (25.0%) discontinued prematurely after a mean of 3.3 (SD = 0.6) weeks in the study (Table 1). Reasons for withdrawal were unknown (lost to follow-up, N = 1), and adverse events (N = 2; headache for 1 participant and drowsiness for the other). The observed mean outcome measures at last post-baseline visit and at week 16 (for the 9 completers) along with the analysis of change in outcome measures are presented in Table 2. Both the longitudinal and end point analyses revealed a statistically significant decrease in mean frequency of binge eating episodes, and a significant improvement in all the other items (Table 2). A high degree of compliance was observed in completing the diaries. At study termination, all patients (100% of recruited patients) reduced the number of binge eating episodes per week, and 7 participants achieved remission of binge eating (58.3%). There was no statistically significant correlation between change in BW and binge episode frequency.
86
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
Table 1 Clinical characteristics and measures by participant. Baseline
1 2 3 4 5 6 7 8 9 10 11 12
At the end of the study
Gender
Age (years)
Duration of BED (years)
Comorbid mood and/or anxiety disorders
Weekly binge eating episode f requency
Body weight (kg)
BMI
Weeks of trial completed
Weekly binge eating episode frequency
Body weight (kg)
BMI
F F F F F M F F F F F F
26 45 41 32 63 48 49 49 50 47 37 43
14 26 5 na 47 12 12 19 36 37 27 3
Yes No Yes No Yes No Yes Yes No No Yes Yes
12 14 11 14 7 7 4 10 3 7 3 3
91.0 105.0 102.0 83.9 94.0 99.0 81.5 93.8 97.2 107.0 87.4 72.5
38.4 40.9 46.4 30.4 35.6 34.4 31.8 33.2 38.9 40.3 35.9 26.0
3 16 16 16 3 16 16 4 16 16 16 16
4 0 0 1 0 0 0 6 0 0 0 0
90.5 101.0 97.0 79.5 94.8 98.5 82.7 93.9 93.6 105.0 88.5 68.1
38.2 39.3 44.1 28.9 35.9 34.4 31.3 33.3 37.4 39.4 36.4 24.4
Eleven participants were women and one was a man. Seven out of 12 participants (58.3%) had comorbid mood and/or anxiety disorders [lifetime mood disorders: participants number 3, 7, 8, 11, and 12; actual mood disorder: participant number 1; actual generalized anxiety disorder: participant number 5]. BED, binge eating disorder; BMI, body mass index (weight in kilograms divided by height in m2); F, female; M, male; na: not available.
2009). The efficacy of disulfiram for the treatment of cocaine use disorder and BED may be due to its ability to increase DA levels, thereby normalizing this “hypodopaminergia” (Devoto, Flore, Saba, Bini, & Gessa, 2013; Devoto, Flore, Saba, Cadeddu, & Gessa, 2012; Kosten et al., 2013). Accordingly, a recent study found that nepicastat, a selective competitive inhibitor of DβH, effectively reduced craving for chocolate and motivation for food consumption sustained by appetite or palatability in rats, suggesting that DβH inhibitors may be effective for the treatment of BED and obesity (Zaru, Maccioni, Colombo, & Gessa, 2013). However, an alteration in the taste of food may have also contributed to the reduction in binge eating as three participants in the current study reported a bitter taste, a frequent side effect of disulfiram referred to as a “garlic-like aftertaste” (Suh et al., 2006). This study has several limitations. First, we cannot eliminate the contribution of a placebo response. A recent study found that, after placebo treatment, approximately 40% of BED patients reduce binge eating episodes, and 30% attain cessation (Blom et al., 2014). The higher number of patients who reduced binge eating episodes and attained cessation in the present study suggest that DβH inhibition may have also contributed to these results. Other limitations of the present study are the small number of participants and the short duration of treatment, motivated by the need to evaluate the safety of disulfiram for BED patients. Finally, in the present study, 7 screened subjects withdrew consent and another 3 were not recruited because mental or physical disorders contraindicated disulfiram administration. Moreover, 2 patients
Eleven participants (91.7%) reported side effects. The most common adverse effects reported were drowsiness (N = 9), headache (N = 7), dysgeusia (N = 3), tachycardia (N = 3), dizziness (N = 2), and nausea (N = 2). One patient decreased the disulfiram dose to 200 mg/day because of excessive somnolence. One patient developed a mild disulfiram-alcohol reaction after consumption of an alcoholic beverage. No participant exhibited significant changes in laboratory test results. 4. Discussion The results of this study show that treatment with disulfiram effectively reduced the frequency of binge eating episodes in a sample of BED patients. This effect may be due, at least in part, to DβH inhibition, the mechanism proposed to explain the efficacy of disulfiram in reducing craving for cocaine and cocaine use in patients affected by cocaine use disorder. Indeed, both drugs of abuse and palatable food increase extracellular DA in the “reward” system, and the subjective perception of pleasure is related to the availability of DA for D2 receptor stimulation within these regions (Mitchell, Roerig, & SteffenK, 2013; Pani et al., 2010). Neuroimaging studies show that both obese individuals and subjects with substance use disorder express fewer D2 receptors than control subjects, suggesting a common “reward deficiency syndrome” (Barry, Clarke, & Petry, 2009). Underexpression of D2 receptors could lead to a propensity for compensatory compulsive engagement in rewarding behaviors, such as drug use and eating (Barry, Clarke, & Petry,
Table 2 Outcome measures before and after 16 weeks of treatment with disulfiram and analysis of change in outcome. Longitudinal analysisa
Mean
BE BW BMI CGI-S VAS BES ZUNG SF-12
Baseline n = 12
Last observation n = 12
7.9 92.8 36.0 4.1 92.1 23.0 37.3 33.3
0.9 91.0 35.2 1.4 62.9 10.6 28.2 38.3
± ± ± ± ± ± ± ±
1.2 2.9 1.6 0.2 4.6 1.7 2.8 2.0
± ± ± ± ± ± ± ±
0.6 2.9 1.5 0.3 10.4 2.8 2.0 1.6
b
Week 16 n = 9 0.1 90.4 35.1 1.1 50.6 7.4 27.9 39.5
± ± ± ± ± ± ± ±
0.1 3.4 1.7 0.1 10.2 2.2 1.9 1.2
c
End point analysisb
Estimate [95% CI]
p value
Estimate [95% CI]
p value
−7.4 [−8.7, −6.2] −2.4 [−3.2, −1.7] −1.0 [−1.4, −0.7] −3.0 [−3.6, −2.4] −35.4 [−48.9, −21.9] −14.9 [−18.7, −11.1] −9.3 [−12.9, −5.7] +5,6 [+2.9, +8.4]
b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001
−7.0 [−9.5, −4.5] −1.8 [−3.3, −0.3] −0.8 [−1.4, −0.2] −2.7 [−3.5, −1.8] −29.2 [−52.8, −5.6] −12.4 [−17.7, −7.1] −9.1 [−14.1, −4.2] +5.1 [+2.3, +7.8]
b.001 .02 .01 b.001 .02 b.001 .002 .002
BE, number of episodes of binge eating per week; BW, body weight (in kilograms); BES, Binge Eating Scale score [a 16-item scale used to assess the severity of binge eating behavior with a total score varying from 0 to 46; (non-binging b17; moderate binging: 18 − 26; severe binging: ≥27)]; BMI, body mass index (weight in kilograms divided by height in m2, normal value b 25); CGI-S: Clinical Global Impression-S, rating scale for clinical global impression of severity of binge eating disorder (BED), with a total score ranging from 1 (no BED) to 7 (the most severe BED); SF-12, score achieved in a 12-item questionnaire used to measure the quality of life [total score varies from 12 to 47 (12 = the worst quality of life; 47 = the best quality of life)]; VAS, score achieved in a Visual Analogue Scale of food craving (0 = no craving and 100 mm = the worst craving)]; ZUNG, score achieved in a 20-item scale used to assess the severity of depressive symptoms [total score varies from 20 to 80; scores N50 are indicative of significant depression)]. a Only those outcomes assessed at each study visit were included into the longitudinal analyses. b last observation end point was defined using last observation carried forward. c Week 16 end point was available for only those participants that completed the study.
A.M.G. Farci et al. / Eating Behaviors 16 (2015) 84–87
discontinued the study, 1 participant reduced the dose, and 1 participant developed a mild disulfiram-alcohol reaction. These data suggest that the use of disulfiram in the treatment of BED patients may be limited by side effects or by the risk of exacerbation of psychotic disorders in subjects already suffering by these disorders. In conclusion, disulfiram was found to be effective in reducing the frequency of binge eating episodes however it also induced side effects in the majority of BED patients, suggesting that it may be useful for the treatment of BED but that its use may be limited by side effects. Longerterm placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability. Role of funding sources Disulfiram and pregnancy tests were supplied by AFOM Dipendenze srl and Confarma srl, respectively. AFOM Dipendenze srl and Confarma srl had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. Contributors Drs. Gessa, Farci, and Agabio designed the study and wrote the protocol. Drs. Farci, Agabio, Piras, Murgia, and Mrs. Chessa assessed patients as per study protocol. Dr. Restivo conducted the statistical analysis. All authors contributed to and have approved the final manuscript. Conflict of interest All the authors declare that they have no conflicts of interest. Acknowledgements The authors express sincere gratitude to Drs. Ilaria Cerina, Olga Curreli, Silvia Mercuro, Romina Naitana, and Elisa Tronci for their contribution to the conduction of the study, and Mr. David Cushley for language editing of the manuscript.
References American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association (Text Revision (DSM-IV-TR)). Barry, D., Clarke, M., & Petry, N.M. (2009). Obesity and its relationship to addictions: Is overeating a form of addictive behavior? American Journal of Addictions, 18, 439–451, http://dx.doi.org/10.3109/10550490903205579. Barth, K.S., & Malcolm, R.J. (2010). Disulfiram: An old therapeutic with new applications. CNS & Neurological Disorders Drug Targets, 9, 5–12, http://dx.doi.org/10.2174/ 187152710790966678. Blom, T.J., Mingione, C.J., Guerdjikova, A.I., Keck, P.E., Jr., Welge, J.A., & McElroy, S.L. (2014). Placebo response in binge eating disorder: A pooled analysis of 10 clinical trials from one research group. European Eating Disorders Review, 22, 140–146, http://dx.doi.org/ 10.1002/erv.2277. Devoto, P., Flore, G., Saba, P., Bini, V., & Gessa, G.L. (2013, Jan 7). The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates
87
psychostimulant-induced dopamine release in the prefrontal cortex. Addiction Biology, http://dx.doi.org/10.1111/adb.12026. Devoto, P., Flore, G., Saba, P., Cadeddu, R., & Gessa, G.L. (2012). Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex. Psychopharmacology, 219, 1153–1164, http://dx.doi.org/10.1007/s00213-011-2447-5. Grilo, C.M., White, M.A., Barnes, R.D., & Masheb, R.M. (2013). Psychiatric disorder co-morbidity and correlates in an ethnically diverse sample of obese patients with binge eating disorder in primary care settings. Comprehensive Psychiatry, 54, 209–216, http://dx.doi.org/10.1016/j.comppsych.2012.07.012. Hald, J., & Jacobsen, E. (1948). A drug sensitizing the organism to ethyl alcohol. Lancet, 6539, 1001–1004. Koob, G.F., & Volkow, N.D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35, 217–238, http://dx.doi.org/10.1038/npp.2009.110. Kosten, T.R., Wu, G., Huang, W., Harding, M.J., Hamon, S.C., Lappalainen, J., et al. (2013). Pharmacogenetic randomized trial for cocaine abuse: Disulfiram and dopamine β-hydroxylase. Biological Psychiatry, 73, 219–224, http://dx.doi.org/10.1016/j. biopsych.2012.07.011. Lin, H.Y., Huang, C.K., Tai, C.M., Lin, H.Y., Kao, Y.H., Tsai, C.C., et al. (2013, Jan 2). Psychiatric disorders of patients seeking obesity treatment. BMC Psychiatry, 13(1), http://dx.doi. org/10.1186/1471-244X-13-1. McElroy, S.L., Guerdjikova, A.I., Mori, N., & O'Melia, A.M. (2012). Current pharmacotherapy options for bulimia nervosa and binge eating disorder. Expert Opinion on Pharmacotherapy, 13, 2015–2026, http://dx.doi.org/10.1517/14656566.2012. 721781. Mitchell, J.E., Roerig, J., & Steffen, K. (2013). Biological therapies for eating disorders. The International Journal of Eating Disorders, 46, 470–477, http://dx.doi.org/10.1002/eat. 22104. Pani, P.P., Trogu, E., Vacca, R., Amato, L., Vecchi, S., & Davoli, M. (2010). Disulfiram for the treatment of cocaine dependence. The Cochrane Database of Systematic Reviews, 1, CD007024, http://dx.doi.org/10.1002/14651858.CD007024.pub2. Pelchat, M.L. (2009). Food addiction in humans. The Journal of Nutrition, 139, 620–622, http://dx.doi.org/10.3945/jn.108.097816. Skinner, M.D., Lahmek, P., Pham, H., & Aubin, H.J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: A meta-analysis. PLoS One, 9, e87366, http://dx.doi.org/ 10.1371/journal.pone.0087366. eCollection 2014. Suh, J.J., Pettinati, H.M., Kampman, K.M., & O'Brien, C.P. (2006). The status of disulfiram: A half of a century later. Journal of Clinical Psychopharmacology, 26, 290–302. Treasure, J., Claudino, A.M., & Zucker, N. (2010). Eating disorders. Lancet, 375, 583–593, http://dx.doi.org/10.1016/S0140-6736(09)61748-7. Umberg, E.N., Shader, R.I., Hsu, L.K., & Greenblatt, D.J. (2012). From disordered eating to addiction: The “food drug” in bulimia nervosa. Journal of Clinical Psychopharmacology, 32, 376–389, http://dx.doi.org/10.1097/JCP.0b013e318252464f. Volkow, N.D., Wang, G.J., & Baler, R.D. (2011). Reward, dopamine and the control of food intake: Implications for obesity. Trends in Cognitive Sciences, 15, 37–46, http://dx.doi. org/10.1016/j.tics.2010.11.001. Ware, J., Jr., Kosinski, M., & Keller, S.D. (1996). A 12-Item Short-Form Health Survey: Construction of scales and preliminary tests of reliability and validity. Medical Care, 34, 220–233. Zaru, A., Maccioni, P., Colombo, G., & Gessa, G.L. (2013). The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats. The British Journal of Nutrition, 110, 1524–1533, http://dx. doi.org/10.1017/S0007114513000743. Zung, W.W. (1965). A self-rating depression scale. Archives of General Psychiatry, 12, 63–70.
