Safety and Efficacy of Different Combinations of Zonisamide-CR Plus Bupropion-SR to Treat Uncomplicated Obesity
Condition: Obesity
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine which of seven combinations of Zonisamide CR and
      Bupropion SR gives the best weight loss and is safe and well tolerated for the treatment of
      obesity not associated with the complications of obesity such as diabetes. In a previous
      study, the combination of zonisamide and bupropion SR was shown to be effective for weight
      loss compared to either zonisamide, bupropion SR alone or placebo. It is thought that by
      adjusting the doses of each drug, giving zonisamide in a controlled release (CR) form and
      increasing the doses more slowly, more weight loss and less side effects can be attained.
    

Detailed description: 
      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.
    

Intervention name(s): Zonisamide CR and Bupropion SR; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Zonisamide SR and Bupropion SR; Identical placebo
Intervention MeSH terms: Zonisamide; Bupropion
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment