Introduction

Obesity is a serious and growing global problem, with the prevalence increasing rapidly in both developed and developing countries (1). In the United States, it is estimated that overweight and obesity combined (BMI 25 kg/m²) affect 60% of the population, and 33% of U.S. adults are obese (BMI 30 kg/m²) (2). This statistic reflects a marked increase since the late 1970s, when the combined prevalence of overweight and obesity was 47% , and the prevalence of obesity was 15% (2, 3). The increase in type 2 diabetes in the U.S. population reflects the trend in obesity (4). Obesity rates in the European countries are somewhat lower (10% to 30% ) than those in the U.S. population, but an obesity prevalence of 15% to 30% has been reported even in developing countries, such as Uruguay, Iran, and Morocco (5, 6, 7).

This epidemic of obesity has serious consequences for public health, increasing the prevalence of type 2 diabetes (8), hypertension (9), dyslipidemia (9), coronary artery disease (10), atrial fibrillation (11), osteoarthritis (12), cancer, and birth complications (1). With an increasing degree of overweight and obesity, mortality from all obesity-related causes, including cancer and cardiovascular disease, has increased (1).

Dietary restriction, especially in combination with exercise programs and behavioral modification, remains the preferred initial treatment approach to weight reduction in obese subjects (13). Such approaches are often effective in the short term, but long-term results have generally been disappointing. Those who lose weight through dietary restriction and behavioral modification typically regain about two thirds of the lost weight within 1 year and almost all of it by the end of 5 years (14). The major problem in maintaining energy balance is the combination of a sedentary lifestyle and abundant availability of highly palatable inexpensive food.

The neurotransmitter dopamine has long been known to play a role in a variety of reward signals. Dopamine activates five known receptor subtypes: D1 and D5 receptors belonging to the D1-like class, which stimulates adenylyl cyclase, and D2, D3, and D4 receptors belonging to the D2-like class, which inhibits adenylyl cyclase (15). A role for D1-like receptors in food intake has been established in animal models (16, 17). Manipulation of dopaminergic transmission in the nucleus accumbens can affect ingestive behavior and appetitive motivation. Other brain regions, such as the ventromedial hypothalamus, may also be important because D1 receptor expression in this region is up-regulated in obese Zucker rats (18). A related aspect of feeding behavior that depends on D1 receptors is palatable food preference. Acute treatment with a prototype D1/D5 antagonist decreased consumption of preferred flavors in rats (19), and D1 receptor knockout mice showed reduced sucrose reinforcement (20). A role of D1/D5 receptors in influencing the reward stimulus produced by cocaine has been suggested in humans with acute administration of ecopipam (SCH 39166), a selective D1 and D5 receptor antagonist that blunts the euphoric effects of cocaine self-administration (21, 22); however, chronic administration either failed to attenuate or enhanced the subjective effects of cocaine (23, 24), and a clinical trial found no efficacy for treating cocaine dependence (unpublished data). Based on the ability of D1/D5 antagonists to affect the reward stimulus produced by palatable foods in rodents, ecopipam was studied for the potential to enhance and maintain weight loss in obese human subjects.

Preclinical studies of ecopipam in several animal models, as well as Phase 2 clinical studies, suggested that this compound was likely to be an effective, well-tolerated weight loss treatment; however, in the course of the Phase 3 clinical trials, there were unexpected treatment-emergent psychiatric adverse events including depression, anxiety, and suicidal ideation. The sponsor decided that these adverse events warranted cessation of the clinical trials and discontinuation of the development program. Because of the status of this compound, we found it irrelevant to report these studies separately, and we here report the major findings from the clinical trials in Phases 2 and 3. This information may contribute to a better understanding of the role of dopamine D1 and D5 receptors in the control of energy balance and depression.

Research Methods and Procedures

All Phase 2 and 3 studies were conducted according to the Declaration of Helsinki and were approved by independent ethics committees or institutional review boards at each site. The designs were multicenter, randomized, double-blind, parallel-group comparisons of the efficacy and safety of ecopipam and placebo in obese subjects. Subjects were non-diabetic except for Study 3.3, which required subjects to have type 2 diabetes (Table 1). All subjects provided written informed consent. The Phase 2 study (Study 2.1) was conducted at 19 centers (2 U.S.; 17 non-U.S.). Of the Phase 3 studies, Study 3.1 was conducted at 55 centers (6 U.S.; 49 non-U.S.), Study 3.2 at 24 U.S. centers, and Study 3.3 at 27 centers (15 U.S.; 12 non-U.S.). The Phase 2 study consisted of 12 weeks of double-blind treatment and 2 weeks of follow-up. In each Phase 3 study, an initial 4-week single-blind run-in phase during which subjects received placebo preceded a 52-week double-blind treatment phase. After the double-blind phase, subjects could continue on open-label ecopipam 100 mg daily for an additional 52 weeks.

Table 1. - Overview of methodology of ecopipam studies.

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Participants

In each study, subjects had to adhere to study requirements. Women had to be non-lactating and of non-childbearing potential or agree to practice effective contraceptive methods. Subjects had to be 18 years of age for all Phase 3 studies. In Studies 3.1 and 3.2, subjects had to have a BMI between 30 and 45 kg/m² inclusive at screening. Inclusion and exclusion criteria unique to Studies 2.1 and 3.3 are given in Table 2.

Table 2. - Inclusion and exclusion criteria unique to Studies 2.1 and 3.3.

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Subjects were excluded in all studies if they were pregnant, had a known hypersensitivity to ecopipam, had clinical laboratory test results outside normal limits that were clinically unacceptable to the investigator and/or sponsor, or had participated in a clinical trial and/or received an investigational drug within 30 days before screening or study start. Subjects were excluded if they had 1) a severe or unstable medical condition (e.g., recent surgery, stroke, myocardial infarction, or malignancy), epilepsy, known electroencephalograph abnormalities, renal disease, neutropenia (neutrophil count of <1500 mm³), or liver disease (viral or alcohol-induced hepatitis) or 2) obesity caused by an identifiable metabolic or endocrinologic syndrome (e.g., Cushing's, Prader-Willi, or Laurence-Moon-Biedl syndromes). Subjects in the Phase 3 studies were excluded for Parkinson's disease, gastric bypass surgery within 1 year of screening, transaminase levels at least three times the upper limits of normal, known history of drug or alcohol dependence, having participated in a clinical trial with ecopipam or resided in the same household with a participant in a clinical trial with ecopipam, or having taken a prohibited medication, including other anti-obesity medications, within 60 days before screening. In Studies 2.1, 3.1, and 3.2, subjects with a severe or unstable psychiatric condition (e.g., schizophrenia, dementia, or bipolar disorder) were disallowed; in Studies 3.1 and 3.2, subjects were excluded for diabetes or hypertension requiring drug therapy.

Procedures

In the Phase 2 study, subjects who met the criteria for entry were randomly assigned to one of four treatment groups: 10, 30, or 100 mg of ecopipam or placebo. Randomization was performed at Visit 1 in a 1:1:1:1 ratio according to a computer-generated code. Subjects self-administered ecopipam hydrochloride tablets or identical placebo tablets orally each day at bedtime for 12 weeks. Subjects could continue hypolipidemic treatment started before the study. Outpatient visits were scheduled at Visit 1, at Weeks 2, 4, 8, and 12, and at the follow-up visit at Week 14. Treatment compliance was checked at the Week 4, 8, and 12 visits.

In the Phase 3 studies, subjects who met the criteria for entry and completed the 4-week run-in phase were randomly assigned on Day 1 to treatment groups in a 1:1:1 ratio (Study 3.1) or 1:1 ratio (Studies 3.2 and 3.3). Subjects were stratified based on weight change (loss of <2 or 2 kg) during the run-in phase. In all three studies, subjects self-administered ecopipam hydrochloride tablets or identical placebo tablets orally at bedtime for 52 weeks during the double-blind phase. Daily ecopipam doses were 50 or 100 mg in Study 3.1 and 100 mg in Studies 3.2 and 3.3. No dose modification was permitted during the double-blind phase. Subjects could continue dyslipidemic medications in all studies and oral hypoglycemic and anti-hypertensive medications in Study 3.3. Outpatient visits were scheduled on Day 1 and at Weeks 2, 4, 8, 12, 16, 22, 28, 34, 40, 46, and 52. Study medication was counted at each visit to confirm compliance. At study termination, the study plan was modified to include two additional safety visits after the 30-day follow-up visit: one at 60 days and one at 90 days after the subjects' last dose.

In all studies, subjects also participated in a program designed for weight reduction that included a prescribed diet with a daily energy intake 500 to 600 kcal below a subject's estimated individual energy requirement. Every 4 (Phase 2) or 2 weeks (Phase 3) for the duration of the trials, including the run-in phase, subjects were expected to attend dietary counseling sessions during which exercise was also encouraged. For the Phase 3 studies, weekly dietary counseling for the first 16 weeks was permitted.

Efficacy and Safety Variables

For the Phase 2 study, the primary efficacy endpoint was the proportion of responders in each treatment group. A responder was a subject who achieved at least a 5% reduction in body weight from baseline at week 12 or within 7 days of the treatment stop date, if discontinued. Secondary efficacy variables were the proportion of subjects who achieved at least a 10% reduction in body weight from baseline at week 12 or at the last visit and the average weight loss in each treatment group.

For the Phase 3 studies, the primary efficacy variable was the distribution of percentage weight loss at the end of 52 weeks of double-blind treatment. Focus was placed on the proportion of subjects with 5% and 10% weight loss from baseline (randomization to study drug). Secondary endpoints included mean weight loss (change in kilograms and percentage change) from baseline and from screening at treatment endpoint; proportion of responders for both 5% and 10% categories at each visit; mean weight loss (change in kilograms and percentage change) from baseline at each visit; and mean change and percentage change from baseline in fat loss (estimated by bioimpedance as a surrogate measure) and in blood glucose, plasma lipids, hemoglobin A_1c, and blood pressure at treatment endpoint. Additional secondary efficacy variables measured at treatment endpoint included mean change and percentage change from baseline in C-peptide in Study 3.2 and in plasma insulin in Studies 3.2 and 3.3, and proportion of subjects that required upward or downward titration of oral hypoglycemic agents from baseline, proportion of subjects that required insulin therapy, mean change and percentage change in waist circumference from baseline, and mean change in quality-of-life domains from baseline in Study 3.3. Because the secondary efficacy data for the Phase 3 studies were never analyzed, these data are not reported.

At each study visit, subjects were questioned about the occurrence and severity of any adverse events. Reported events were graded for the probability of relationship to the study drug. Adverse events included the onset of new illnesses and the exacerbation of pre-existing conditions.

Statistical Analyses

In the Phase 2 study, a sample size of 50 subjects per group provided 80% power at a 5% level of significance if the proportion of responders was 35% for an active treatment group and 10% for placebo. All analyses were based on the intention-to-treat population, which consisted of all subjects randomized to treatment. Overall comparison was performed using the Cochran-Mantel-Haenszel test. Pairwise comparison of each ecopipam dose with placebo was performed using Dunnett's multiple comparison procedure. Changes from baseline in body weight were evaluated at Weeks 4, 8, 12, and 14 using a two-way ANOVA, with treatment and investigator effects in the model.

In Studies 3.1 and 3.2, approximately 400 randomized subjects per treatment group were required to detect weight loss differences against placebo rates of 20% for a 5% weight loss and of 10% for a 10% weight loss with 100% power and a 5% level of significance at 52 weeks. In Study 3.3, approximately 200 randomized subjects per treatment group were required to detect weight loss differences against placebo rates of 20% for a 5% weight loss and of 10% for a 10% weight loss with 93% power and a 5% level of significance at 52 weeks.

In all Phase 3 studies, the primary efficacy population was the intention-to-treat population, which consisted of all randomized subjects with a baseline and at least one post-baseline evaluation. Because of the sponsor's decision to terminate the program prematurely, these studies were truncated at 52 weeks. The primary efficacy variable was analyzed using the Kolmogorov-Smirnov test. If this test was significant at the 5% level, ² tests were used for response rates based on weight losses of 5% and 10% following a stepwise approach. Changes from baseline in body weight were evaluated at Weeks 12, 28, and 52 using a two-way ANOVA, with center and treatment effects in the model.

Adverse events were classified by body system and tabulated by treatment group. To quantify the occurrence of psychiatric adverse events after study medication was stopped and to examine which subjects with psychiatric adverse events had previous psychiatric medical histories, a number of psychiatric adverse events were selected for analysis in the Phase 3 studies. These selected adverse events included panic attack, panic attack aggravated, depression, depression aggravated, psychotic, psychotic worsened, anxiety, anxiety aggravated, suicidal ideation, suicide attempt, nervousness, emotional lability, agitation, agitation aggravated, aggressive reaction, agoraphobia, delusion, homicidal ideation, neurosis, paranoid reaction, psychosis, personality disorder phobic disorder, obsessive-compulsive disorder, and suicide (accomplished).

Results

Study Populations and Efficacy

Study 2.1: A Phase 2, Multicenter, 12-week Dose-ranging Study for the Treatment of Obesity.

There was no difference in demographic characteristics between the ecopipam-treated and placebo groups (Table 3). A greater proportion of subjects receiving ecopipam than placebo completed the 12-week trial (83.8% vs. 76.6% ). In the intention-to-treat population, ecopipam produced significantly greater weight loss than placebo (Figure 1, Study 2.1). After 12 weeks, weight loss was 1.7% , 2.3% , 2.6% , and 3.6% in the placebo and ecopipam 10-, 30-, and 100-mg groups, respectively. Only the response rate (weight loss of 5% ) achieved with ecopipam 100 mg was greater than that in the placebo group at treatment endpoint (p < 0.01; Table 4).

Figure 1.

Mean percentage change in body weight from baseline by treatment week for the Phase 2 and 3 studies. Study 2.1 was a 12-week study; all other studies were 52 weeks. Data are means standard deviation based on the number of subjects remaining in the studies (completer populations). Significant differences from placebo are indicated by an asterisk (p < 0.01, ANOVA).

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Table 3. - Demographic and baseline characteristics for Phase 2 and 3 studies: intention-to-treat population.

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Table 4. - Reduction in body weight by dose group in the Phase 2 study at treatment endpoint^*: intention-to-treat population.

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Study 3.1: A Phase 3, Multicenter, Three-arm, 52-week Efficacy and Safety Trial Preceded by a 4-week Placebo Run-in Phase for the Treatment of Obesity.

The demographic distribution was very similar among the three treatment groups (Table 3). Weight loss changes over 52 weeks in these groups are shown in Figure 1 (Study 3.1). Both 50- and 100-mg doses of ecopipam produced a greater weight loss than placebo from Week 12 throughout the trial. After 52 weeks, weight loss was 1.4% , 4.7% , and 5.1% for placebo and ecopipam 50 and 100 mg, respectively (p < 0.01); however, there was no significant difference between the two ecopipam doses. At the end of treatment, the results were very similar to those at 52 weeks: 0.9% , 4.4% , and 4.6% weight loss for placebo and ecopipam 50 and 100 mg, respectively (p < 0.01). A greater proportion of subjects also lost 5% to 10% and >10% of body weight from baseline on ecopipam than on placebo (Figure 2). The difference became significant (p < 0.01) from Week 12 onward. At Week 52, the proportion of subjects who had lost >10% was 8.3% , 16.7% , and 18.1% in the placebo and ecopipam 50- and 100-mg groups, respectively (both ecopipam doses vs. placebo, p < 0.01).

Figure 2.

Distribution of percentage weight loss (<5% , 5% to 10% , or >10% ) from baseline by treatment week for the Phase 3 studies. Data are means based on the number of subjects remaining in the studies (completer populations). Significant differences from placebo are indicated by an asterisk (p 0.01, ² test).

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Study 3.2: A Phase 3, Multicenter, Two-arm, 52-week Efficacy and Safety Trial Preceded by a 4-week Placebo Run-in Phase for the Treatment of Obesity.

Ecopipam 100 mg produced significantly more weight loss than placebo from 12 weeks (Figure 1, Study 3.2) and 4 kg more after 52 weeks (6.2% vs. 2.0% , p < 0.01). The results were very similar at the end of treatment (4.2% vs. 0.6% , p < 0.01). In the ecopipam group, at least twice as many subjects achieved 5% to 10% and >10% weight loss than in the placebo group (Figure 2). After 52 weeks, 23.4% vs. 9.3% lost >10% in the ecopipam and placebo groups, respectively (p < 0.01).

Study 3.3: A Phase 3, Multicenter, Two-arm, 52-week Efficacy and Safety Trial Preceded by a 4-week Placebo Run-in Phase for the Treatment of Obese Type 2 Diabetic Subjects.

Because of the early termination of this trial, only one of the enrolled obese type 2 diabetic subjects was recorded as completing the 52-week trial, and the mean duration of the active double-blind treatment was only 12 to 13 weeks (ecopipam, 146 89 days; placebo, 149 85 days); however, 85% attained the 12-week visit and 40% attained the 28-week visit. The weight loss for the completers is presented in Figure 1 (Study 3.3). At the end of treatment, ecopipam produced greater weight loss than placebo (3.3% vs. 0.9% , p < 0.01). In the cohort of 40% of diabetic subjects who completed 28 weeks of treatment, weight loss was 3.9% and 1.0% in the ecopipam and placebo groups, respectively (p < 0.01). Moreover, 9.2% vs. 0% lost >10% of initial body weight in the two groups (p < 0.01; Figure 2).

Safety

Safety was evaluated for all randomized subjects in all studies. The overall incidence of treatment-emergent adverse events was slightly higher in the ecopipam-treated groups than in the placebo groups in the Phase 2 and 3 studies (Tables 5and 6).

Table 5. - Most frequently reported treatment-emergent adverse events occurring during the double-blind phase and during follow-up of the Phase 2 study.

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Table 6. - Most frequently reported treatment-emergent adverse events occurring during the double-blind phase of Phase 3 studies.

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The most frequently reported treatment-emergent adverse events during the double-blind phase and during follow-up in the Phase 2 study were headache, viral infection, and somnolence. In the Phase 3 studies, the most frequently reported treatment-emergent adverse events during the double-blind phase were upper respiratory tract infection, headache, insomnia, depression, fatigue, anxiety, and somnolence. The majority of adverse events in all studies were mild or moderate.

During the double-blind phase of the Phase 3 studies, the overall incidence of selected psychiatric adverse events was higher in ecopipam-treated subjects than in subjects given placebo (ecopipam 31% vs. placebo 15% ; Table 7). Of those subjects who had medical histories of psychiatric conditions before they began the study, 68 (15% ) of 445 ecopipam-treated subjects and 28 (18% ) of 159 placebo subjects experienced at least one of the selected psychiatric adverse events. (The majority of these subjects reported their psychiatric histories in follow-ups subsequent to screening.) The incidence of depression and anxiety in the ecopipam-treated group was twice that in subjects given placebo, and there were unexpected reports of suicidal ideation. The relative risk for suicidal ideation in the ecopipam-treated group compared with the placebo group was 1.57 [ 95% confidence interval (CI),¹ 1.33 to 1.85; ² = 12.32, p < 0.001] . Although the overall incidence of selected psychiatric adverse events decreased substantially after the cessation of treatment, a higher incidence of these adverse events was still observed in the ecopipam-treated group compared with the placebo group from the last dose to the final 90-day follow-up.

Table 7. - Selected psychiatric adverse events occurring during the double-blind phase to the final 90-day follow-up of Phase 3 studies.

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No deaths were reported in the Phase 2 study. Other serious adverse events occurred in eight subjects (six ecopipam and two placebo). Only three subjects in the Phase 2 study showed serious psychiatric disorders: anxiety and insomnia in one subject treated with 10 mg of ecopipam and insomnia or somnolence in two placebo-treated subjects. No serious psychiatric adverse events were observed in subjects treated with 30 or 100 mg of ecopipam. The overall incidence of study discontinuation because of treatment-emergent adverse events was 17 (9% ) of 185 ecopipam-treated subjects and 7 (11% ) of 64 subjects given placebo. The most frequently reported adverse events associated with discontinuation in both groups were nausea and insomnia (2% vs. 3% placebo for both adverse events).

Five deaths occurred in the Phase 3 studies (Table 8). In Study 3.1, one subject in the 50-mg ecopipam group died of myocardial infarction on Day 540 (177 days after the last ecopipam dose). In Study 3.2, two placebo-treated subjects died: one of cardiorespiratory arrest on Day 72 and one on Day 164 after a cardiac arrest (asystole) that occurred on Day 135. Both deaths occurred 9 days after the last placebo dose. In Study 3.3, two subjects treated with 100 mg of ecopipam died: one of cardiac arrest on Day 136 (16 days after the last ecopipam dose) and one by suicide on Day 333 (99 days after the last ecopipam dose).

Table 8. - Deaths, other serious adverse events, and discontinuations because of adverse events in the Phase 3 studies.

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During the double-blind phase of the Phase 3 studies, almost one half of the other serious adverse events that occurred in the ecopipam-treated group were associated with psychiatric disorders (Table 8). Psychiatric adverse events also accounted for more than one half of the discontinuations because of treatment-emergent adverse events in the ecopipam group. These differences, which were not observed in Phase 2, were considered significant and contributed to the sponsor's decision to discontinue the program.

Discussion

The major difficulty in obesity management is not to induce weight loss, but to subsequently maintain it. In the Phase 3 studies, ecopipam 100 mg produced a clinically relevant weight loss of 3.1% to 4.3% more than that achieved in the placebo groups at 52 weeks (Figure 1). Ecopipam also substantially increased the proportion of subjects who achieved a 5% to 10% or >10% weight loss (Figure 2). Subjects randomized to ecopipam showed greater maintenance of weight loss over 52 weeks compared with placebo-treated subjects.

A recent meta-analysis was performed on 11 orlistat trials and 5 sibutramine trials lasting 1 year or longer by the Cochrane database system (25). Compared with placebo, orlistat-treated patients lost 2.7 kg (95% CI, 2.3 to 3.1 kg) or 2.9% (95% CI, 2.3% to 3.4% ) more weight, and patients on sibutramine experienced 4.3 kg (95% CI, 3.6 to 4.9 kg) or 4.6% (95% CI, 3.8% to 5.4% ) greater weight loss. The number of patients achieving 10% weight loss was 12% (95% CI, 8% to 16% ) higher with orlistat compared with placebo and 15% (95% CI, 4% to 27% ) higher with sibutramine therapy than with placebo. The two Phase 3 studies with ecopipam in non-diabetic subjects (Studies 3.1 and 3.2) showed 3.7% and 4.2% greater weight loss with ecopipam 100 mg than with placebo. The proportion of subjects in these two studies who lost >10% of their initial body weight with ecopipam 100 mg was 9.8% and 14.1% greater than in the placebo groups. Therefore, the efficacy of ecopipam compares favorably with the two agents presently available for the long-term treatment of obesity.

The magnitude of the weight loss achieved with ecopipam is clinically relevant for the prevention of complications in obese subjects. A number of studies have shown that even a moderate weight loss of 3% to 5% maintained over 3 to 4 years is sufficient to prevent the majority of new cases of type 2 diabetes (26, 27). In both the Finnish Diabetes Prevention Trial and the American Diabetes Prevention Program, obese subjects with impaired glucose tolerance were instructed to use a calorically restricted low-fat diet, to be physically active at least 25 to 30 minutes daily, and to attend regular counseling sessions with nutritionists. Weight loss after 1 year was 5% to 7% in these studies. The relative risk reduction of diabetes was 58% . Even a weight loss of <3% achieved with orlistat was recently shown to be sufficient to reduce the incidence of type 2 diabetes in non-diabetic obese patients (28).

Although a limited number of subjects in the current studies received ecopipam treatment beyond 1 year, there was no evidence of drug tolerance or loss of efficacy over time; the difference in weight loss between the ecopipam and placebo groups was maintained over the course of the study. Consequently, ecopipam has the potential to be used for effective weight maintenance in obese patients at high risk of developing type 2 diabetes and possibly other complications of obesity.

Ecopipam seemed to be at least as effective in producing weight loss in type 2 diabetics as in non-diabetic obese subjects. It is generally recognized that weight loss achieved with a given treatment is less in type 2 diabetics than in non-diabetic obese patients (13), whether the treatment is diet and behavior modification or weight loss agents, such as orlistat and sibutramine. Although the mechanism for the lower weight loss outcome in type 2 diabetics is poorly understood, achieving and maintaining a desirable body weight is a major goal in the management of type 2 diabetes. Weight loss dramatically improves glycemic control, lipid profile, and blood pressure in obese individuals with type 2 diabetes (American Diabetes Association recommendations). Although more difficult, weight loss in type 2 diabetic patients can be produced and maintained, and the health benefits are more substantial. Notably, ecopipam produced a weight loss of 4% in the Phase 3 trial in obese type 2 diabetic subjects (Figure 1, Study 3.3), substantially increased the proportion of subjects who achieved a weight loss of 5% to 10% , and particularly increased the proportion losing >10% (Figure 2). More research is needed to explore the possibility that the dopaminergic mechanism of action may be of special importance in obese type 2 diabetic subjects.

The Phase 3 clinical studies were discontinued because of concerns over the different rates of psychiatric effects between the ecopipam and placebo groups, including anxiety and panic attacks and, in particular, the relative increase in reports of depression and suicidal ideation. More psychiatric adverse events occurred in the Phase 3 ecopipam group (31% ) than in the placebo group (15% ). Approximately 2% of the ecopipam group and 1% of the control group reported suicidal ideation. It is unclear whether the medication worsened a pre-existing condition or induced a new condition because there was no direct assessment of depression, depressive symptoms, or suicidal ideation before treatment.

In a recently published study of weight reduction in obese patients with dyslipidemia, rimonabant, a selective cannabinoid 1 receptor blocker, resulted in a 1.7% and 2.9% incidence of depression at doses of 5 and 20 mg, respectively, compared with a 0.6% incidence in the placebo group (29). Depression was indeed the chief adverse event leading to discontinuation of the trial, although the mechanism for depression is unknown. Because cannabinoid 1 antagonists prevent cannabinoid-mediated potentiation of dopamine release in the nucleus accumbens (30) and because ecopipam blocks dopaminergic signaling through D1/D5 receptors, the pathways through which ecopipam and rimonabant affect both food intake and mood may be related.

Obesity has been shown to be associated with depression in the general population and in clinical samples (31), especially in women and in severely obese men (32). Treatment-seeking obese individuals are especially prone to depression. Depression has been reported to range up to 48% for these individuals and to increase as the severity of obesity increases (33, 34). Obese women are also 20% more likely to report suicidal ideation and 23% more likely to have made a suicide attempt in the last year than non-obese women (35), whereas obese men generally have not been found at risk to experience suicidal ideation or suicide attempts (36). In the Phase 3 studies with ecopipam, reports of suicidal ideation during the double-blind phase of treatment were twice as common in men than in women; however, the relatively low incidence of suicidal ideation in these studies makes it too speculative to draw a general conclusion about sex differences.

Conversely, weight loss in the obese is associated with improvement in depressive symptoms as measured by the Beck Depression Inventory (31). Larger weight losses after Lap-Band surgery are associated with greater improvements in Beck Depression Inventory scores. If weight loss typically results in improvements in mood across methods of weight loss (37, 38), a treatment that results in sustained weight loss would be expected to improve instead of worsen the mood of the participants. Previous human studies of ecopipam in cocaine-abusing patients did not report any psychiatric adverse effects including depression or suicidality (22, 23, 39); however, these studies were all of short duration and do not offer sufficient assurance that depression may not occur with the more extended treatment that would be required to treat obesity.

The mechanistic basis for an increase in depression with chronic D1 antagonist treatment is unclear. In one study, cerebrospinal fluid levels of the dopamine metabolite homovanillic acid were found to be significantly lower in hospitalized patients who had attempted suicide than in patients hospitalized for non-psychiatric conditions (40). In addition, an increase in limbic D1 receptor expression has been reported in a validated animal model of depression (41). Together, these studies suggest that up-regulation of D1 receptor expression may be a mechanism to compensate for reduced synaptic dopamine concentrations in depressed individuals. In addition, strong aversive and stressful conditions, such as restraint, electrical shock, and anxiogenic drugs, increase dopaminergic neuronal firing and dopamine release in rodents, suggesting that dopaminergic activity may be recruited to help manage or to recover from the effects of stress and aversiveness. Blockade of D1 receptors that would otherwise be stimulated by this compensatory increase in dopaminergic activity might provide a mechanistic explanation for an increased incidence of depression after chronic D1/D5 antagonist treatment. Further research into the potential benefit of D1 antagonists may well consider the interplay among these mechanisms in the context of careful systematic assessment and monitoring of these changes during treatment.

The mechanism of the psychiatric adverse events may also be linked to the mechanism by which D1 receptors affect feeding behavior. Pre-clinical studies have shown that dopamine acting through D1 receptors decreases an animal's desire to work for food rather than the animal's desire to ingest food (42). In an experiment in which D1 receptor knockout mice exhibited reduced lever pressing for a sucrose reward, home cage sucrose consumption was similar to that of wild-type controls (20). This finding suggests that loss of D1 receptors affects motivation but not appetite. Dopaminergic lesions have repeatedly been shown to affect motivation to perform behaviors, such as foraging for food, indicating that activation of dopamine systems mediates goal-directed behavior. Long-term D1 receptor blockade may decrease the drive toward goal-directed behavior and possibly contribute to the psychiatric effects, such as those observed in this study, in addition to the desired loss of body weight. Alternatively, dopamine may mediate other functions that impact psychiatric state.

Little is known about the contribution of D5 receptors to dopaminergic control of reward signal processing, food intake, or psychiatric states. In the absence of antagonists that discriminate between D1 and D5 receptors, the specific contributions of D1 and D5 receptors to the effects of a non-selective antagonist, such as ecopipam, have not been elucidated. If future studies suggest that D5 receptors mediate the psychiatric adverse events while selective D1 receptor antagonists confer benefits, such as weight loss, selective D1 receptor antagonists would remain pharmacologically interesting agents for the treatment of non-diabetic obese patients and obese type 2 diabetic subjects.

Where does the field go from here? Although ecopipam has been discontinued from further studies in obesity because of the risk of increased depression during treatment, it is still unknown whether other members of the same drug class may possess a different interaction profile. A careful risk/benefit analysis in the context of the downstream effects of progressive obesity would be required to address the overall use of the D1 antagonist mechanism.

Notes

¹ Nonstandard abbreviation: CI, confidence interval.

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Acknowledgments

We thank Susan Nick for help in preparing the manuscript, Dr. Vicki Coffin for scientific contribution to the idea of using a D1/D5 antagonist for the treatment of obesity, and Usha Barai and Dr. Pabak Mukhopadhyay for statistical support. These trials were sponsored by Schering-Plough Research Institute, Kenilworth, NJ. The members of the Ecopipam Obesity Study Group are: Mortoglou Anastasios, MD, Athens, Greece; James W. Anderson, MD, Lexington, KY, USA; Arne Astrup, MD, Dr Med Sci, Copenhagen, Denmark; Richard Lee Atkinson, Jr, MD, Madison, WI, USA; Raymond Baker, MD, Vancouver, BC, Canada; Jean Bergeron, MD, MSc, Ste-Foy, Québec, Canada; Marshall B. Block, MD, Phoenix, AZ, USA; George A. Bray, MD, Baton Rouge, LA, USA; Jacques Bringer, MD, Mountpellier, France; Jean-Marcel Brun, MD, PhD, Dijon, France; Osvaldo J. Brusco, MD, PhD, Buenos Aires, Argentina; David G.P. Carey, MBBS, Sydney, Australia; Gérard Cathelineau, MD, Paris, France; Franco Contaldo, MD, Naples, Italy; Sandro Corigliano Carrillo, MD, Lima, Peru; Troy Donahoo, MD, Denver, CO, USA; Carlos A. Dujovne, MD, Overland Park, KS, USA; Graham Charlston Ellis, MBChB, Somerset West, South Africa; Giuliano Enzi, MD, Padova, Italy; Guillermo Fanghänel Salmon, MD, Mexico City, Mexico; Nicholas Finer, MBBS, Harpenden, Herts, United Kingdom; John Paul Foreyt, PhD, Houston, TX, USA; Xavier Formiguera Sala, MD, Badalona, Spain; Arthur Frank, MD, Washington, DC, USA; Ken Fujioka, MD, San Diego, CA, USA; Alberto Galvão-Teles, MD, PhD, Lisbon, Portugal; Pedro Pablo Garcia Luno, MD, Seville, Spain; W. Thomas Garland, MD, Lawrenceville, NJ, USA; Dominique Garrel, MD, Montréal, Québec, Canada; Jean-François Gautier, MD, Paris, France; Larry I. Gilderman, DO, Pembroke Pines, FL, USA; Sergio Arturo Godinez Gutierrez, MD, Guadalajara, Mexico; Jorge González Barranco, MD, Mexico DF, Mexico; Vinicio Granados, MD, Zacapa, Guatemala; Frank L. Greenway, MD, Baton Rouge, LA, USA; Steven M. Haffner, MD, San Antonio, TX, USA; Vojtch Hainer, MD, PhD, Prague, Czech Republic; Kathleen M. Hall, MD, MPH, Minneapolis, MN, USA; Hans J. Hauner, MD, Berlin, Germany; David Heber, MD, PhD, Los Angeles, CA, USA; Robert J. Heine, MD, PhD, Amsterdam, The Netherlands; Robert R. Henry, MD, San Diego, CA, USA; Steven B. Heymsfield, MD, New York, NY, USA; James O. Hill, PhD, Denver, CO, USA; Priscilla Hollander, MD, Dallas, TX, USA; Michael D. Jensen, MD, Rochester, MN, USA; Steven Emanuel Kahn, MBChB, Seattle, WA, USA; Mehmood Ahmad Khan, MD, Minneapolis, MN, USA; B.F. Klapp, MD, Berlin, Germany; Peter G. Kopelman, MD, London, England; Michel Krempf, MD, Nantes, France; Robert F. Kushner, MD, Chicago, IL, USA; Karen S.L. Lam, MD, Hong Kong, China; Ben Lasko, MD, Weston, Ontario, Canada; Michael E.J. Lean, MD, Glasgow, Scotland; Walter Ling, MD, Los Angeles, CA, USA; Tulio Lopez Lara, MD, Caracas, Venezuela; Bernhard H. Ludvik, MD, Vienna, Austria; Morton H. Maxwell, MD, Sherman Oaks, CA, USA; James M. McKenney, PharmD, Richmond, VA, USA; Nicholas H.E. Mezitis, MD, New York, NY, USA; Basilio Moreno Esteban, MD, Madrid, Spain; William J. Mroczek, MD, Falls Church, VA, USA; Giorgio Noseda, MD, Mendrisio, Switzerland; Patrick Mahlen O'Neil, PhD, Charleston, SC, USA; Detlef Pape, MD, Essen, Germany; Miguel Angel Pasquel Andrade, MD, Quito, Ecuador; Maureen Passaro, MD, Washington, DC, USA; Piyush Patel, MBBS, Mississauga, Ontario, Canada; Aldo Pinchera, MD, Pisa, Italy; F. Xavier Pi-Sunyer, MD, New York, NY, USA; Denis Prud'homme, MD, MSc, Québec, Québec, Canada; Marieta Rebelo, MD, Lisbon, Portugal; Stephan Rössner, MD, PhD, Huddinge, Sweden; Ana Sastre, MD, Madrid, Spain; Jürgen Scholze, MD, PhD, Berlin, Germany; Sherwyn Schwartz, MD, San Antonio, TX, USA; Simona Scumpia, MD, Austin, TX, USA; Edward M. Sellers, MD, PhD, Toronto, Ontario, Canada; Arya M. Sharma, MD, Berlin, Germany; Lars Sjöström, MD, PhD, Göteborg, Sweden; Diane K. Smith, MD, Augusta, GA, USA; Stephen R. Smith, MD, Baton Rouge, LA, USA; William B. Smith, MD, New Orleans, LA, USA; Soren Snitker, MD, PhD, Baltimore, MD, USA; James W. Snyder, MD, Las Vegas, NV, USA; Norman G. Soler, MD, PhD, Springfield, IL, USA; Katharine Steinbeck, MBBS, PhD, Sydney, Australia; Elisabeth Steinhagen-Thiessen, MD, Berlin, Germany; Carl Stroh, PhD, Vancouver, BC, Canada; Jorge Eduardo Tartaglione, MD, Buenos Aires, Argentina; Hermann Toplak, MD, Graz, Austria; Søren Toubro, MD, Copenhagen, Denmark; Alejandro C. Ugarte, MD, Buenos Aires, Argentina; Luc F. Van Gaal, MD, PhD, Antwerp, Belgium; Giancarlo Viberti, MD, London, England; Jaime E. Villena Chavez, MD, Lima, Peru; Karel Vondra, MD, DSc, Prague, Czech Republic; Thomas A. Wadden, PhD, Philadelphia, PA, USA; Stuart R. Weiss, MD, San Diego, CA, USA; Donald R. Wessen, MD, Berkley, CA, USA; Klaas R. Westerterp, PhD, Maastricht, The Netherlands; Paul Fredrick Whitsitt, MD, Oshawa, Ontario, Canada; Rena R. Wing, PhD, Providence, RI, USA; Hannele Yki-Jarvinen, MD, PhD, Helsinki, Finland; Grace Yung-Li, MD, San José, Costa Rica; Carlos Zavala, MD, Santiago, Chile; James H. Zavoral, MD, Edina, MN, USA; Olivier Ziegler, MD, DSc, Nancy, France; and Joel Zunszein, MD, Bronx, NY, USA.