Safety and Efficacy of Different Combinations of Zonisamide-CR Plus Bupropion-SR to Treat Uncomplicated Obesity

Over the past few years, knowledge of the pathways and neural circuits that sense body energy stores has increased dramatically. In particular, it has been shown that the melanocortin system, a group of neuronal circuits in the arcuate nucleus of the hypothalamus, is the "final common pathway" for most energy state signals, and that melanocortin signaling is necessary for normal control of food intake and energy expenditure. Stimulation of POMC neurons by serotonergic and dopaminergic agents results in release of α-, β- and γ-MSH through the action of prohormone convertase-2 with a consequent decrease in appetite.A second counter-regulatory system that inhibits POMC activation is β-endorphin, which binds to a mu-opioid receptor (MOP-R) and acts as an auto-inhibitory "brake" on the activity of the melanocortin circuits. Bupropion is an approved antidepressant that blocks reuptake of serotonin and dopamine. This stimulates secretion of both α -MSH and β-endorphin. α -MSH binds to melanocortin receptors which in turn results in appetite suppression and increased energy expenditure. β-endorphin, however, binds to a mu-opioid receptor (MOP-R) and inhibits the activity of the melanocortin circuits. Zonisamide has multiple effects that may protect against seizures, including blockade of sodium channels, and reducing voltage dependent inward (T type) calcium currents, leading to neuronal stabilization. In addition to these actions, however, it is known to increase 5-hydroxytryptophan and dopamine levels, simultaneously stimulating α -MSH release while inhibiting AGRP release. Thus, the combination of bupropion and zonisamide stimulates the melanocortin system while blocking an important feedback inhibitory pathway. The combination of zonisamide 400 mg/day and bupropion SR 300 mg/day has been shown to be more effective for weight loss than either monotherapy or placebo in subjects with uncomplicated obesity. The hypothesis for the current trial is that greater efficacy and improved tolerability can be achieved by adjusting the doses and titration of both bupropion SR and zonisamide, and by giving zonisamide in a controlled release (CR) formulation.