Table 2.

Studies that reported hypodopaminergic state in binge eating

Study characteristics	Study purpose	Participant characteristics	Measurement	Results
Frank et al. 52 Case–control	To test the associations between dopamine and learning in BN patients	20 purging type BN female (age: 25.2 ± 5.3; BMI: 22.6 ± 5.7) 23 healthy control, matched for age and level of education (age: 27.2 ± 6.4; BMI: 21.5 ± 1.2) In BN patients, weekly binge episodes 23.5; illness duration: 74.2 months Among the BN patients, 12 have one or more of the following: major depressive disorder, social phobia, anxiety disorder, PTSD	The temporal difference model: individuals learned to associate different taste stimulus (sucrose solution, no solution, and artificial saliva) with a paired conditioned visual stimulus Event-related fMRI: after breakfast (8-9am) BOLD signal	BN individuals had reduced brain response in the ventral putamen, amygdala, insula and orbitofrontal cortex compared to controls for both taste conditions Binge/purge frequency significantly predicted reduced dopamine response in the BN for the left insula, substantia nigra, left amygdala, right amygdala, right insula, left ventral putamen, and right ventral putamen These results strongly suggest reduced dopamine reactivity in BN is related to illness severity
Vaz-Leal et al. 86 Case–control	To compare 24-h urinary excretion of dopamine between BN patients and healthy controls	75 female with purging type BN (age: 22.9 ± 2.7; BMI: 22.5 ± 1.6) 30 healthy female Caucasian controls (age: 23.6 ± 3.3; BMI: 22.0 ± 1.6) All BN patients were severe: the mean of binging at assessment was 1 per day Exclusion: substance abuse	Urinary 24-h excretion of dopamine was quantified using column chromatographic methods	BN patients had significantly lower 24-h urinary excretion of dopamine
Broft et al. 47 Case–control	To assess striatal D2 receptor density and striatal dopamine release in patients with BN	16 BN female: (age: 24.4 ± 5.1; BMI: 21.7 ± 1.4) 17 healthy control female: (age: 24.9 ± 4.2; BMI: 21.4 ± 2.0) BN patients: duration of illness 7.8 years Exclusion: current or past Axis I disorders, diagnosis of current ADHD or past history of anorexia nervosa, alcohol or substance abuse, active suicidal ideation, use of fluoxetine and other psychoactive medications, ongoing medical or neurological illness, pregnancy	PET scanning after a standardized meal Two scans with [11C]raclopride: a baseline scan and a second scan which began 60 min following administration of methylphenidate Eating disorder examination (EDE-12)	The difference in D2 receptor binding potential between the patient and control groups was not statistically significant Low striatal dopamine response to methylphenidate are present at significant levels only in the putamen, but not in the ventral striatum A statistically significant association between striatal dopamine release and frequency of objective binge episodes: the lower the striatal dopamine response to methylphenidate, the greater the frequency of binge eating in the previous 28 days
Majuri et al. 49 Case–control	Compare dopamine function between BED and healthy controls	7 BED female (age: 49.4 ± 5.1; BMI: 30.9 ± 6.6) 17 healthy controls (age: 43.3 ± 11.1; BMI: 24.8 ± 2.1) BN patients: duration of illness 18.1 years None of the subjects were using medications known to have effects on the dopamine system	PET with [18F]fluorodopa [18F]fluorodopa scan at 1430–1530 h after a standardized lunch	A lower dopamine synthesis capacity in BED compared with controls in the nucleus accumbens with the cluster extending to the caudate and putamen BED is characterized by a widespread reduction in striatal dopamine synthesis capacity
Frieling et al. 57 Case–control	To examine the peripheral expression of dopaminergic genes in patients suffering from eating disorders	24 female with BN (age: 25.8 ± 7.7; BMI: 22.6 ± 2.6) Duration of illness: 9.0 ± 5.8 years 30 age-matched healthy women (age: 22.0 ± 4.5; BMI: 21.7 ± 3.7)	Total RNA was extracted from whole frozen EDTA-blood using a standard phenol–chloroform-extraction in Qiazol (Qiagen), followed by column-purification with Rneasy Mini Kit (Qiagen)	BN showed an elevated peripheral expression of dopamine transporter mRNA and a downregulation of the DRD2 expression when compared with the controls
Thaler et al. 61 Cross-sectional	Examine dopamine polymorphisms acting upon postsynaptic receptors in women with bulimia-spectrum eating disorders DRD2 TaqA1 rs1800497, DRD4 7R, COMT rs4680, DAT1	269 bulimic women with full-blown and sub-threshold bulimia (age: 25.9 ± 6.7; BMI: 22.7 ± 3.8) 65.1% BN-purging subtype, 5.2% BN-nonpurging subtype, and 29.7% Eating Disorder Not Otherwise Specified Number of binge episodes per month was 25.82 (SD = 35.71) 52.7% of the sample were using a psychoactive medication	Genomic DNA was extracted from blood leukocytes using the FelxiGene DNA Kit (Qiagen) Eating disorders examination	Participants with the Val/Val genotype had higher levels of binge eating than those with a Met allele Participants with the DAT 10/10 genotype reported higher levels of binge eating than did those with any 9-repeat allele
Corwin et al. 56 Animal model	Test whether dysregulation of dopamine system using dopamine D1 and D2 agonist and antagonist influence binge eating	Male Sprague–Dawley rats A rat model of binge-type eating in which non-food-deprived rats with brief intermittent (3 days/week) access to an optional source of dietary fat binge on the fat relative to rats with brief daily access to the same fat	D1 agonist (SKF 81,297) targeting PFC—M2 region D1 antagonist (SCH 23,390) targeting PFC—M2 region D2 agonist (quinpirole) targeting PFC—M2 region D2 antagonist (eticlopride) targeting the Cg1/M2 Micropunched tissue from the VTA, NA core and shell, central nucleus of the amygdala, and PFC were collected and analyzed for relative mRNA expression using the comparative threshold cycle method	VTA Before binge, gene expression for tyrosine hydroxylase, the dopamine transporter, and the D2-like receptor was higher in the binge rats than the control rats Within intermittent access, tyrosine hydroxylase was significantly higher before binge but returned to control level after binge Gene expression for the D1-like receptor was significantly lower in the intermittent access rats relative to D No difference in amygdala or nucleus accumbens PFC Neither the D1 agonist nor the D1 antagonist infused into the M2 region of the PFC affected shortening intake When the D2 agonist was infused into the M2 region, shortening intake was significantly reduced after the highest dose in both intermittent access and binge eating rats D2 blockade with eticlopride stimulated intake in the intermittent access rats, but was without effect in the control rats Conclusion The initially-elevated VTA dopaminergic gene expression may contribute to binge initiation The PFC, and D2 receptors in particular, functions as a behavioral brake to limit bingeing
Amorim-Barbosa et al. 84 Case–control	Evaluate COMT activity in patients with BN and BED	10 BN 10 BED (BMI: 39.3 ± 1.4) 10 control subjects matched for age and gender (BMI: 22.5 ± 0.9) Individuals treated with antidepressant were analyzed in separate groups Exclusion: history of tabagism and drug consumption	EDE-Q COMT activity was determined by the ability of enzyme preparations to methylate adrenaline to metanephrine in crude homogenates and soluble-COMT	Patients with BN or BED showed increased soluble-COMT activity when compared with controls
Chawla et al. 55 Animal model	Examine the gene expression of dopamine receptors (Drd1, Drd2, Drd4) in binge eating rats	44 male, young adult Sprague–Dawley rats Intermittent access binge group (binge, n = 28), daily access group (DAILY, n = 8) and chow controls (CON, n = 8) Rats in the binge group were further divided into binge eating prone (BEP) and binge eating resistant (BER) categories	Total RNA was extracted from tissue punches using the RNeasy Lipid Tissue Mini kit (QIAGEN)	PFC (OFC, mPFC, FrC) OFC: significantly lower expression of Drd1 in BEP as compared to CON group OFC: significantly lower expression of Drd4 in BEP as compared to CON group mPFC: significantly greater expression of Drd1 in BEP as compared to CON group mPFC: significantly lower expression of Drd4 in BEP as compared to DAILY rats Nucleus accumbens Lower Drd2 expression in BEP rats as compared to CON rats A negative correlation between the average shortening consumed in last week of binge paradigm and the nucleus accumbens Drd2 expression
Heal et al. (2017) Animal model	To investigate the dopaminergic systems (dopamine receptors, dopamine transporter, dopamine concentration) in the brains of binge-eating and control rats	Lean, female Wistar rats BED was induced by intermittent access (Unpredictable intermittent two-hour access to chocolate over a period of 28 days) 20 BED group and 20 non-binge eating control group	Whole brains were removed and striata were dissected before being frozen on dry ice Eight- or 10-concentration radioligand saturation binding analysis was used to measure tissue receptor density and affinity	Striatal D1 receptors was significantly reduced by 38.7% in the binge-eating group (in the caudate putamen, but not nucleus accumbens) Binge-eating did not alter the density or affinity of D2 receptors in the striatum compared with controls Binge-eating did not alter either the density of striatal DAT sites or the affinity of DAT sites in the brains of the rats No significant differences between the concentrations of dopamine in the striatum, frontal cortex or hypothalamus the rate of dopamine turnover were not significantly altered in either the striatum or prefrontal cortex
Gervasini et al. 62 Cross-sectional	Evaluate associations between the Val158Met polymorphism in the COMT gene and general psychopathological symptoms	74 BN female (BMI: 24.6 ± 6.9) 30 BED female (BMI: 34.3 ± 10.2) 51.8% were being treated with antidepressant Exclusion: dementia, mental retardation, schizophrenia, Turner’s syndrome, other neurological disorders and underlying endocrine pathologies	Symptom Checklist 90 Revised Genomic DNA was isolated from peripheral blood leukocytes	BN patients who carried the Val-allele scored higher in all nine scales and three global indices of the Symptom Checklist 90 Revised questionnaire
Grob et al. 76 Randomized, double-blind, placebo-controlled, crossover design	To test dopamine function in remitted subjects with BN who performed a reinforcement-learning task after catecholamine depletion	19 women who had BN remission (age: 25.2 ± 3.5; BMI: 21.7 ± 2.9) 28 healthy control women (age: 25.8 ± 3.6; BMI: 22.1 ± 2.1) Exclusion: lifetime diagnosis of psychosis, major medical or neurological illness, psychoactive medication exposure in the past 6 months, lifetime history of substance dependence, pregnancy, suicidal ideation	Catecholamine depletion achieved by oral administration of alpha-methyl-paratyrosine (AMPT) Thirty hours after the first AMPT/placebo administration, participants completed a 25-min probabilistic reward task Examination-Questionnaire (EDE-Q) was assessed at (0, 26, and 30 h after the first AMPT/placebo administration) and on the 3 subsequent days (54, 78, and 102 h after the first AMPT/placebo administration)	Following catecholamine depletion, rBN subjects (but not controls) showed reduced responsiveness to rewards leading to an inability to modulate behavior as a function of reinforcement history This DA-mediated deficit was not associated with time in remission from BN, suggesting that reduced reinforcement learning might represent a stable, trait-like feature of BN
Grob et al. 77 Randomized, double-blind, placebo-controlled, crossover design	To examine the effect of catecholamine depletion on bulimic symptoms in remitted BN and controls	18 female who had been in remission from BN for at least 6 months (age: 25.6 + 4.7; BMI: 21.2 + 1.7) 31 controls who had no history of any psychiatric disorder (age: 25.8 + 3.8; BMI: 22.4 + 2.2) Exclusion: current Axis I psychiatric disorders, a lifetime diagnosis of psychosis, major medical or neurological illness, psychoactive medication exposure within the previous 6 months, lifetime history of substance dependence, pregnancy, suicidal ideation	German Version of the Eating Disorder Examination—Questionnaire Measurements were conducted immediately before the first AMPT or placebo intake (prechallenge) and 26, 30, 54, 78, 102 h after the first AMPT or placebo administration The time frame was divided into the controlled environment (time points 26 and 30 h) and the uncontrolled environment (time points 54, 78, and 102 h)	Under controlled environment, rBN subjects reported more bulimic symptoms in the conditions in which they received AMPT compared with the placebo condition The results indicate that catecholamine depletion induced a transient reappearance of mild eating disorder symptoms in remitted subjects with a history of BN, which is in line with the desensitized dopaminergic theory
Guerdjikova et al. 79 12-week randomized, double blind, parallel-group, and flexible-dose study	To evaluate the effect of Lisdexamfetamine dimesylate (LDX) on binge eating	50 adults (92% women; age: 37.7 ± 8.9; BMI: 39.8 ± 9.3) who display ≥ 3 binge eating days/week were randomized to LDX (n = 25) or placebo (n = 25) Mean baseline weekly binge eating days/week was 4.2 (1.2); binge eating episodes/week was 5.1 (3.1) Exclusion: current anorexia nervosa or bulimia nervosa, current suicidal ideation, receipt of a psychological or weight loss intervention for BED, substance use disorder, a lifetime history of psychosis, mania, or hypomania; a clinically unstable medical illness; receipt of psychotropic medication	Participants were randomized to receive LDX or placebo in a 1:1 ratio Participants were evaluated at least twice during the screening period; after 1, 2, 3, 4, 6, 8, 10, and 12 weeks during the treatment period; and 1 week after study medication discontinuation	Comparing the baseline-to-endpoint change score differences, LDX was associated with statistically significant decreases in binge eating days/week, binge eating episodes/week
McElroy et al. 80 Randomized, double-blind, parallel-group, placebo-controlled clinical trial	To examine the efficacy and safety of lisdexamfetamine dimesylate to treat moderate to severe BED	259 patients with moderate-to-severe BED (81.5% female; age: 38.7 ± 10.2; BMI: 34.9 ± 5.3) Exclusion: current bulimia nervosa, anorexia nervosa, ADHD, or another psychiatric disorder; a lifetime history of bipolar disorder or psychosis; psychological or weight-loss interventions; use of a psychostimulant; cardiovascular disease; substance abuse; antipsychotics, antidepressants	Participants were randomized (1:1:1:1) to receive placebo or 30, 50, or 70 mg/d of lisdexamfetamine dimesylate Changes in binge eating behaviors were measured at week 11	At week 11, lisdexamfetamine dimesylate treatment with 50 and 70 mg/d, but not 30 mg/d, demonstrated a significant decrease (compared with placebo) in weekly binge eating days per week and binge eating episodes per week
Mueller et al. 53 Double-blind, crossover design	To identify the role of dopamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa	17 female participants in remission from BN (rBN, at least 4 months) (age: 29.6 ± 8.9; BMI: 21.6 ± 2.3) 21 female healthy volunteers (age: 27.3 ± 9.4; BMI: 24.2 ± 3.3) Did not exclude major depression, using psychological medications	Participants received once catecholamine depletion induced by alpha-methyl-paratyrosine (AMPT) and once sham depletion in a randomized order During fMRI, participants performed monetary incentive delay (MID) task The monetary earning in this task indicates the effectiveness of integrating reward magnitudes and effort costs to guide behavioral performance	Healthy controls earned less money (reduced the ability to integrate effectively reward magnitudes and effort costs to guide behavioral responses) following AMPT relative to the sham condition, whereas the monetary earning of rBN participants was not influenced by AMPT The reward–effort integration indicated by the monetary earning was found to be already reduced in rBN participants in the sham condition, the longer the duration of active illness, the less money they earned in the sham condition
Grilo et al. 81 12-week double-blind, parallel-group treatment	Evaluate the efficacy and safety of two fixed doses of dasotraline (4 and 6 mg/d) in adults with BED	485 moderate-to-severe BED patients (female: 83.9%; age: 37.6; BMI: 34.5) Moderate-to-severe BED: based on a history of ≥ 2 binge eating days per week for ≥ 6 months prior to screening; and patient diary-confirmed criteria of ≥ 3 binge eating days per week for each of the 2 weeks prior to study baseline Exclusion: lifetime history of bulimia nervosa or anorexia nervosa; initiation of a formal weight loss program; a lifetime history of psychotic disorder, bipolar disorder, hypomania, or ADHD; history of moderate-to-severe depression; use of antidepressants, psychostimulants, or mood stabilizers; a history of substance abuse; diabetes, hypertension or cardiovascular disease	Participants were randomized to receive 4 mg/d dasotraline, 6 mg/d dasotraline, or placebo Changes of binge eating were measured at week 12	At week 12, treatment with dasotraline was associated with significant improvement in number of binge eating days per week on the dose of 6 mg/d Dasotraline treatment improved obsessional thoughts related to binge eating and ruminative preoccupations that interfered with daily functioning, and reduced the compulsion to binge eat, increasing patient control and ability to resist the binging urges