Rather than considering OSA as an isolated condition for treatment, it is also important to consider risk/aggravating factors such as obesity, alcohol consumption, cigarette smoking and obstructive nasal pathologies. Furthermore, some of the important resultant morbidities of OSA such as hypertension (discussed above) and neurobehavioral dysfunction, particularly manifesting as excessive daytime sleepiness, also warrant early and direct therapeutic approaches. The roles of anti-obesity drugs, alertness-promoting drugs and other drugs are therefore discussed below.
Obesity predisposes to OSA, progressive weight gain worsens established OSA and weight loss ameliorates the severity of OSA [2,83-86]. Reducing weight may achieve benefit in OSA through improvement to upper airway caliber (by reducing fat deposition in the lateral pharyngeal wall and tongue), by improvement of residual lung volume (and thus of overall lung function) and by reducing whole body oxygen demand [2, 87, 88]. Generally, anti-obesity drugs are not first-line therapy in the treatment of obesity and are usually recommended as supplementary to a dietary and exercise program where such options are practicable. Some therapies such as of the general class of noradrenergic drugs are FDA recommended only for short-term use. Other weight-loss agents such as ephedrine/ephedra combined with caffeine, though effective, have significant safety concerns and are not recommended. A comprehensive overview of the management of obesity, including drug therapy, is beyond the scope of this chapter and the interested reader is referred elsewhere [89-91]. A brief summary only of the major anti-obesity drug options is given here.
That particular psychotropic drugs such as the SSRI antidepressants fluoxetine (see also above), sertraline and fluvoxamine may be useful as weight-loss agents was initially suggested by the unexpected observation of weight loss in trials of these agents in patients treated for neuropsychiatry conditions . Subsequently, randomized controlled trials were specifically designed to assess their efficacy as weight-loss agents in obesepatients without neuropsychiatry co-morbidities. Of these agents, fluoxetine has been the most studied, in obese subjects without attendant co-morbidities , in obese subjects with diabetes [94, 95] and in obese subjects with eating disorders . Short-term (8 weeks) studies in the first group showed an approximate weight loss of about 4 kg compared with placebo, though doubts have surfaced about sustained benefit in longer-term studies. Trials of fluoxetine as a weight-loss agent in obese type 2 diabetics have shown mixed results. Fluoxetine has shown to be efficacious and well tolerated in obese patients with binge eating disorder and bulimia nervosa.
Bupropion increases noradrenaline turnover and blocks reuptake of dopamine but does not affect serotonin reuptake. It is used as an antidepressant and to aid smoking cessation. In depressed patients bupropion was noted to engender significant weight loss, and limited weight gain in smoking cessation trials [97, 98]. In studies specifically designed to assess the anti-obesity properties of bupropion in subjects without neuropsychiatric co-morbidities, weight losses of 7.5-13 % of initial weight was achieved after 8-12 months treatment, and was generally well tolerated [99,100].
There has been limited short-term experience as anti-obesity agents with the SSRI citalopram [101,102], and with the serotonin-noradrenaline reuptake inhibitor venlafaxine , and no recommendations can be made re use of these agents solely as anti-obesity therapy in clinical practice.
Topiramate can be described as a broad-spectrum neurotherapeutic agent with multiple modes of action, and its weight-loss promoting activity came to attention in trials of therapy for epilepsy , and explored further in animal experiments [105, 106]. It has also been successfully used in the treatment of obesity associated with eating disorders [107, 108]. As specific weight-loss therapy in one short-term  and one long-term study  in non-diabetics without co-morbid neuropsychiatric conditions, topiramate has been shown to produce a modest dose-related benefit compared to placebo, and with a reasonable side-effect profile.
Zonisamide is an anti-epileptic with serotonergic, dopaminergic and other properties, and also has been associated with weight loss in clinical trials of treatment of seizure disorders . In a single trial to adjudge efficacy as a weight-loss agent in obese individuals without co-morbid neuropsychiatric conditions, zonisamide was well tolerated and associated with a weight loss of 9.2 kg at 32 weeks .
Sibutramine is a specific inhibitor of noradrenaline and serotonin reuptake into nerve terminals, and is believed to inhibit food intake by promoting satiety ; it may also increase thermogenesis [114-116]. Short- and long-term clinical trials of sibutramine in obese subjects documents weight loss of approximately 10 % of initial weight with continued use [117-119]. The main potential adverse effects are increased blood pressure and heart rate, and the drug is contraindicated in cardiac conditions, and in patients who have had stroke, or are using monoamine oxidase inhibitors or SSRIs. In patients with obesity and OSA, sibutramine has a similar weight-loss profile and predictable associated improvements in indices of sleep-disordered breathing . Sibutramine is FDA approved for long-term use to aid/maintain weight loss.
Orlistat alters fat metabolism by inhibiting pancreatic lipases with consequent increased fecal fat excretion. Long-term trials confirm orlistat's ability to promote approximately 10 % weight loss [120,121], and to help prevent weight regain . Main side effects are discomforting gastrointestinal symptoms such as excessive borborygmi, cramps, flatus, etc. Orlistat also may produce an improvement in lipid profile unexplained by the degree of weight loss . It is FDA approved for long-term use.
A number of peptides including leptin, glucagon-like peptide-I and peptide YY induce weight loss in experimental animals and in humans [124, 125] but are not currently approved for use by the FDA or other regulatory bodies in the clinical treatment of obesity.
Alertness-promoting drugs have a well-recognized primary role in the treatment of conditions in which excessive daytime sleepiness (EDS) is a prominent or the major symptom causing disablement, conditions such as narcolepsy and idiopathic hyper-somnolence. The use of such medications in other disorders where EDS persists despite treatment of the underlying pathophysiology with directed treatments (e.g. , nCPAP in OSA) is controversial. Alertness-promoting drugs (also known as stimulants) can be classified as sympathomimetic (examples include the amphetamines, methylphenidate, pemoline) or non-sympathomimetic (modafinil, caffeine).
The action of modafinil, though presently not fully understood, is thought to be mediated largely by dopamine ; it is possible that it may also affect the his-taminergic system  and inhibit release of GABA in the hypothalamus , influence serotonin release and, at least in rats, reduce noradrenaline reuptake . In the case of persisting EDS in CPAP-treated OSA patients, modafinil has been shown to improve Epworth Sleepiness Scale (ESS) scores and multiple sleep latency test (MSLT) results compared to placebo in a short-term trial of therapy . Other short-term studies have documented improvements in sleep-related functional health status and ESS scores , or improved the frequency of lapses of attention during psychomotor vigilance performance testing . On the other hand, another study of modafinil in this context did not show improvements in MSLT latency or ESS score, but did show a marginal improvement in the latency of the maintenance of wakefulness test (MWT) . A recent longer (12 week) study has also confirmed the useful role of modafinil in these circumstances, documenting improvements in MWT latencies, ESS score and overall clinical condition .
Sabeluzole andNMDA receptor antagonist AR-R15896AR Glutamate may be the neuromediator responsible for ventilatory stimulation during acute hypoxia, and thereby may contribute to the ventilatory instability present during sleep in OSA. It was postulated that it may be possible to decrease ventilatory variability in OSA by the use of the glutamate antagonist sabeluzole. In a small study of sabeluzole in OSA patients, compared to placebo there was no overall improvement in oxygenation, although higher levels of the drug were associated with improved sleep levels of oxygen in some individual patients . In a study examining hypoxemia-induced glutamate release into the CNS, the potential benefit of antagonism of glutamate effects mediated by postjunctional NMDA receptors was examined in a placebo-controlled double-blind study in 15 patients with OSA. However, the NMDA receptor antagonist AR-R15896AR did not significantly affect AHI or oxygen saturation variables in this context .
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