1806 showed beneficial effects on triglyceride levels and HbA1c. No major side effects have been reported or safety issues raised so far. However, taken the known side effects of both drugs at higher doses (30), it is predictable that authorities will be watchful in the further processes. Indeed, FDA has recently (October 2010) declined to approve Qnexa based on the current data, asking for more study results and more information on possible risks. Bupropion plus Zonisamide (Empatic®) Bupropion (Fig. 7) has been discussed in the previous section. The combination with the anti-epileptic compound zonisamide (Fig. 8) has been reported to have higher efficacy with fewer side effects. Like topiramate, zonisamide is an anti-convulsant compound that has been shown to induce weight loss (114). It is supposed to act via mechanisms that are partly different from those of topiramate, affecting GABA, serotonin, and dopamine-regulated processes (30). In a phase IIb trial lasting 24 weeks, involving 729 obese subjects, mean weight loss with Empatic-360 (bupropion 360 mg/zonisamide 360 mg) was 9.9% and 7.7% with Empatic-120 (bupropion 360 mg/zonisamide 120 mg), respectively. The placebo group lost 1.7% of their body weight (111). In addition, significantly more subjects in the groups receiving the combinations lost ≥5% of their baseline weight as compared with subjects in the placebo group. Adverse events were similar to those reported for each of the individual drugs. This combination is antici- pated to move to phase III testing soon. Bupropion Plus Naltrexone (ContraveR) This third combination of existing drugs combines bupro- pion with the opioid antagonist naltrexone and is developed by the same company (Orexigen Therapeutics, Inc.) as Empatic®. Like bupropion, naltrexone is also already on the market. Synergistic effects were found in preclinical testing and during phase II studies. It has been suggested that the μ- and κ-antagonist naltrexone inhibits a negative feedback loop that limits the α-MSH response of POMC neurons following stimulation by bupropion. The resulting α-MSH then acts as an anorexigenic signal via stimulation of the MCR4 receptor (see also next section). The company has submitted an NDA to the FDA following a series of successful phase III trials that were finished in 2009. In these trials, the combination met the FDA efficacy benchmark causing at least 5% loss of body weight in approximately 50% of patients treated with Contrave-32 (bupropion 360 mg SR+naltrexone 32 mg SR) as com- pared to 16–18% of placebo patients. This was accompa- nied with improvements of cardiometabolic risk factors. The company also announced that the combination shows Witkamp beneficial properties in obese persons with diabetes and obese persons with major depression (115). Serotonin (5-HT) Receptor Ligands The inverse relation between an increased availability of serotonin in certain brain areas and food intake has already been recognized for a long time, for example from the effects of fenfluramine and selective serotonin reuptake inhibitors like fluoxetine. However, due to side effects, non-selective modu- lation of brain serotonin levels were generally not regarded as an attractive target for weight management. During further investigations to untie the different serotonin actions to achieve better selectivity, a number of 5-HT receptors were identified as potential candidates (see (116) for review). Of those, the 5-HT2C and 5-HT6 receptors have so far delivered the most promising candidates. 5-HT2C Agonists The role of the brain 5-HT2c receptors in reducing food intake was discovered by the end of the last century while investigating the mechanisms of action of fenfluramine in rodents (117,118). As a result, several companies started to develop selective 5-HT2C agonists as possible candidates for obesity (116,119). Although a number of compounds have reached phase II testing, selectivity for 5-HT2c over (peripheral) 5-HT2B receptors and the development of tolerance may limit their success (116). However, a promising molecule is lorcaserin (APD356, Fig. 9), a structural analogue of dexfenfluramine. The compound is a selective 5-HT2C agonist with ~15- fold and 100-fold selectivity over that for 5-HT2A and 5- HT2B receptors, respectively (120). Its efficacy has been demonstrated in a number of studies. For example, during a two-week phase II trial with 469 obese persons (BMI 30– 45 kg/m2), lorcaserin caused dose-dependent weight loss up to 3.3 kg (placebo adjusted) in the group receiving lorcaserin 10 mg two times daily. The percentages of patients completing the trial who lost ≥5% of their initial body weight were 2.3, 12.8, 19.5, and 31.2% with placebo, 10 mg per day, 15 mg per day and 10 mg two times daily, respectively (120). After completing a phase III clinical trial program, the company Arena Pharmaceuticals has submit- ted a New Drug Application to the FDA in December 2009, based on data from 18 clinical trials with, in total 8,576 patients, which were evaluated for periods up to two Fig. 9 Lorcaserin, a selective 5-HT2C agonist currently in the registration phase.