Pharmacotherapy for Obesity

Centrally Acting Agents Affecting the Hedonic Control of Food Intake

A second approach to reducing food intake is to target the brain's reward pathways. The reward systems are activated in response to the intake of high-calorie palatable foods and are thought to stimulate intake of these foods even in the absence of nutrient deficit or weight loss.^[85] Pharmacological interventions that alter the reward value of food might therefore be useful in controlling food intake. However, the same systems are thought to be involved in addictive behavior and motivation more generally, and thus drugs targeted at these systems may have profound emotional and behavioral consequences. Physiologically, a single neurotransmitter will usually mediate several different actions or systems but these are physically separated, such as in different neural pathways, which prevents functional overlap. A chemical mimic of the neurotransmitter will necessarily activate all the pathways it participates in and thus obligatorily have several different actions, some of which may be unwanted therapeutically.

Cannabinoid Receptor (CB1) Antagonists

The endocannabinoids are endogenous lipids derived from arachidonic acid, which activate G-protein-coupled cannabinoid receptors (CB). Endocannabinoid signaling within the hypothalamus and mesolimbic system affects food intake. Administration of an endocannabinoid into the ventromedial hypothalamus or the nucleus accumbens of rats causes increased food intake, an effect blocked by a CB1 receptor antagonist.^[86,87] Antagonists of the CB1 receptor have been developed as potential treatments for obesity and several clinical trials using these agents have been carried out.^[88–90]

The first selective CB1 receptor antagonist to be approved to treat obesity was rimonabant (Acomplia®, Sanofi-Aventis). Weight loss of approximately 7% was achieved over a 1-year period in patients treated with this drug.^[88] Reduction in food intake, premeal hunger and desire to eat, with only little effect on satiety, suggested that the CB1 blockade specifically suppressed the motivation to eat.^[91,92] A significant improvement in metabolic comorbidities was also reported. However, shortly after its introduction to the European market, independent reports suggested that other effects of blocking the CB1 system were closely associated with this drug, including depression and suicidal thoughts. Subsequently, when the drug came before the FDA committee in 2007,^[209] the panel voted against its approval, and in January 2009, rimonabant was officially withdrawn from the European market.

A second CB1 antagonist, taranabant, revealed similar efficacy and side effects to rimonabant.^[93–97] Attempts to reduce the drug doses in favor of better tolerability failed.^[98] The psychiatric side effects seen with both drugs were therefore assumed be indicative of the entire class of CB1 antagonists and the development of other advanced CB1 antagonist programs was temporarily suspended by pharmaceutical companies (including the Pfizer CB1 antagonist, otenabant [CP-945,598] and the Bristol Myers Squibb compound, SLV-319).

Cannabinoid receptor antagonists continue to be developed, with the aim of stimulating weight loss by peripheral mechanisms (see the section entitled 'Peripherally acting agents modifying food intake and energy expenditure').

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