5.1. Obesity drugs
Drugs which have been available and licensed for obesity treatment until now are only moderately effective and may have serious side-effects. There is, however, great need for drugs which are on the long term both safe and effective with regard to weight loss and longstanding weight maintenance. Presently, only two drugs are licensed in most Western countries for long term use in obesity management: orlistat and sibutramine.
Orlistat is an inhibitor of gastric and pancreas lipase, resulting in a 30% decrease of the resorption of ingested fats and a similar increase of fecal fat excretion. The drug is virtually not absorbed and thus systemic side effects are absent. The side effects are directly related to the degree of steatorrhea which in turn is dependent of the amount of ingested fat.
Sibutramine is a selective inhibitor of the presynaptical reuptake of serotonin and norepinephrine, leading to enhanced central serotonin and norepinephrine neurotransmission which is associated with decreased sensations of hunger and increased feeling of satiety; besides, sibutramine leads to a slightly enhanced basal metabolic rate (Hansen et al., 1999). Sibutramine has the following side effects: xerostomia, insomnia, obstipation and a mild increase of blood pressure and heart rate.
In a number of randomized, placebo-controlled trials of 1-2 year duration, both drugs are approximately equally effective, leading to a 3-5% more weight loss than placebo, significantly better weight maintenance and a significantly greater number of patients achieving at least 10% of weight loss (Yanovski and Yanovski, 2002); (Haddock et al., 2002).
Other drugs, in some countries licensed for short-term use in obesity management, are amphetamine, its derivatives and related compounds: dexamphetamine, metamphetamine, benzamphetamine, diethylpropion, clobenzorax, fenpropex, phen-dimetrazine, phentermine and mazindol. These anorectic drugs increase the release and action of norepinephrine and dopamine and carry a serious risk of drug dependence and abuse and are therefore not approved in many countries.
Fenfluramine and its dextro-isomer dexfenfluramine both enhance release and inhibit reuptake of serotonin. Despite reasonable efficacy, both drugs have been taken from the market because of serious side-effects (carcinoid-like valvular heart disease and pulmonary hypertension). Other serotonin reuptake inhibitors, such as fluoxetine, are not licensed for obesity treatment, because of insufficient efficacy.
Drugs currently under clinical investigation for use in obesity management are selective P3-sympathicomimetic drugs, the cannabinoid receptor antagonist rimonabant, the anticonvulsant drug topiramate, a NPY-receptor antagonist and a cholecystokinine-A receptor agonist.
Sibutramine has been shown to be effective in treating obesity and binge eating (Appolinario et al., 2002); (Smith and Goulder, 2001); (Finer et al., 2000). Brain sites producing serotonin (the nucleus raphe) and norepinephrine (mainly the locus ceruleus), project widely through the brain, including centers involved in regulation of energy balance. Since another serotonin-reuptake inhibitor, fenfluramine, which has been on the market to treat obesity, requires 5HT2C receptors (Vickers et al., 1999) probably located in POMC neurons (Heisler et al., 2002), one hypothesis might be that sibutramine also acts via this serotonergic system.
The antidepressant drug Fluoxetine, a more selective serotonin reuptake inhibitor, is generally well tolerated and may be an effective treatment option for adolescents with bulimia nervosa. (Kotler et al., 2003). Treatment with fluoxetine in patients with bulimia nervosa improved outcome and decreased the likelihood of relapse. (Romano et al., 2002). Fluoxetine may also prevent relapse in AN. It dimishes associated symptoms of anorexia nervosa following adequate weight restoration (Kim, 2003). Thus, for the treatment response to fluoxetine, genes constituting the serotonin system may play a role. Since serotonin 2C receptors expressed on leptin-sensitive POMC cells mediate at least some of the effects of the reuptake inhibitor fenfluramine on eating behaviour, also the neuropeptidergic genes implicated in the leptin response, are candidate genes for the treatment responsiveness of this class of drugs.
Olanzapine has been evaluated as drug therapy in anorexia nervosa in open label trials. Olanzapine administration was associated with weight gain and maintenance as well as reduced agitation and resistance to treatment (La Via et al., 2000); (Powers et al., 2002; Boachie et al., 2003). Although olanzapine is an atypical antipsychotic that antagonises multiple receptors, it has a relatively high affinity for the serotonin 2C receptor, and may via this route influence energy balance.
Topiramate, an anticonvulsant drug, has anorectic effects. Topiramate may be an effective treatment for binge-eating disorder (Shapira et al.,2000). Topiramate treatment improves multiple behavioral dimensions of bulimia nervosa. Binge and purge behaviors are reduced, and treatment is associated with improvements in self-esteem, eating attitudes, anxiety, and body image(Hedges et al., 2003).
The mechanism of drug action is poorly understood but topiramate has been reported to interact with various ion channel types, including AMPA/kainate receptors and in particular GluR5 kainate receptors (Gryder and Rogawski,
2003). These receptors are widely distributed in brain. It is not known how altered activity of these channels by toporimate could play a role in treating eating disorders.
Pharmacogenetic studies have not been performed yet for the drugs that are prescribed for the treatment of obesity and eating disorders. Only orlistat and sibutramine are accepted pharmacotherapies, whereas for eating disorders drug treatment is still in an exploratory phase. The identification of the neural circuitry involved in regulation of energy balance has now implicated several genes, many of which can be targeted with drugs. These genes are also candidate genes to modify drug responsiveness. Genetic variability (including functional polymorphisms) for many of these candidate genes are known, thus making pharmacogenetic studies feasible.
Genes influence susceptibility for obesity and eating disorders via traits within these complex disorders. Indeed for some of these traits, such as perfectionism, a strong genetic component has been identified. Refinement of (behavioural) traits within complex behaviours is an essential step in order to understand better how genes affect development of eating disorders and obesity (Kas et al., 2003). Identification of genes underlying (behavioural) traits within eating disorders and obesity will paven the way towards refinement in classification of eating disorders and obesity endophenotypes. Different endophenotypes may require different pharmacotherapies. One clear example is the treatment with leptin which is successful only in obese individuals carrying mutations in the leptin gene. Once we understand better how the genes described in this chapter affect human feeding behavior and energy balance, new drug treatment strategies can be developed and pharmacogenetic studies will be helpful to select patients for these drug treatments.
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