Table 2 Studies that reported hypodopaminergic state in binge eating

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