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Chapter 29: Psychopharmacological Treatment

of dietary fat from being absorbed. Higher doses have not been shown to produce more pronounced effects. An over-the-counter formulation of orlistat (Alli) is available as 60-mg capsules—half the dosage of prescription orlistat. Lorcaserin (Belviq) This drug is awaiting approval by the FDA because it appears to have hallucinogenic potential. The exact mechanism of action of lorcaserin is not known, but it most likely decreases food consumption and promotes satiety through selective activation of 5-HT 2C receptors on neurons in the hypothalamus. The effect of multiple oral doses of lorcaserin 15 mg and 40 mg once daily on QTc interval has been evaluated in healthy subjects. The largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 milliseconds, the threshold for regulatory concern. Lorcaserin is absorbed from the gastrointestinal tract, with peak plasma concentration occurring 1.5 to 2 hours after oral dosing. The absolute bioavailability of lorcaserin has not been determined. Lorcaserin has a plasma half-life of approximately 11 hours; steady state is reached within 3 days after twice daily dosing, and accumulation is estimated to be approximately 70 percent. Lorcaserin can be administered with or without food. Lorcaserin hydrochloride is moderately bound (approximately 70 percent) to human plasma proteins. It is extensively metabolized in the liver by multiple enzy- matic pathways, and the metabolites are excreted in the urine. Lorcaserin and its metabolites are not cleared by hemodialysis. It is not recommended for patients with severe renal impairment (creatinine clearance less than 30 mL per minute) or patients with end-stage renal disease. The half-life of lorcaserin is prolonged by 59 percent to 19 hours in patients with moderate hepatic impairment. Lorca- serin exposure (area under the curve) is approximately 22 and 30 percent higher in patients with mild and moderate hepatic impairment, respectively. Dose adjustment is not required for patients with mild to moderate hepatic impairment. No dosage adjustment based on gender is necessary because it did not meaningfully affect the pharmacokinetics of lorcase- rin. No dosage adjustment is required based on age alone. Lorcaserin significantly inhibits CYP2D6-mediated metabolism. Drugs Without U.S. Food and Drug Administration Approval for Weight Loss Topiramate Topiramate and zonisamide (Zonegran) are discussed more fully in Section 29.6, but are mentioned here because both agents can have a substantial effect on weight loss. Topiramate is approved as an antiepileptic drug and for pre- vention in adults of migraine headaches. The degree of weight loss associated with topiramate may be comparable to the weight loss that other FDA-approved antiobesity drugs induce. Small studies and extensive anecdotal reports indicate that topiramate can help to offset weight gain associated with selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotic

be swallowed whole, never crushed, chewed, or cut. The maxi- mum daily dose is 75 mg. Side effects include dry mouth, unpleasant taste, restlessness, anxiety, dizziness, depression, tremors, upset stomach, vomit- ing, and increased urination. Side effects that warrant medical attention include tachycardia, palpitations, blurred vision, skin rash, itching, difficulty breathing, chest pain, fainting, swelling of the ankles or feet, fever, sore throat, chills, and painful uri- nation. Diethylpropion is classified pregnancy Category B and has a low abuse potential. It is listed as a Schedule IV drug by the DEA. Orlistat (Xenical, Alli) Orlistat interferes with the absorption of dietary fats, caus- ing reduced caloric intake. It works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids and are excreted undigested instead. Only trace amounts of orl- istat are absorbed systemically; it is almost entirely eliminated through the feces. The effectiveness of orlistat in promoting weight loss is defi- nite, though modest. When used as part of weight loss program, between 30 and 50 percent of patients can expect a 5 percent or greater decrease in body mass. About 20 percent achieve at least a 10 percent decrease in body mass. After orlistat is stopped, up to a third of people gain the weight they lose. Among the benefits of orlistat treatment are a decrease in blood pressure and a reduced risk of developing type 2 diabetes. The most common subjective side effects of orlistat are gastrointestinal related, and include steatorrhea, flatulence, fecal incontinence, and frequent or urgent bowel movements. To minimize these effects, foods with high fat content should be avoided; a low-fat, reduced calorie diet is advisable. Ironi- cally, orlistat can be used with high-fat content diets to treat constipation that results from treatment with some psychotropic drugs, such as the tricyclic antidepressants. Side effects are most severe when beginning therapy and may decrease in frequency with time. Hepatic and renal injuries are potentially serious side effects of orlistat use. In 2010, new safety information about rare cases of severe liver injury was added to the product label of orlistat. The rate of acute kidney injury is more common among orlistat users than nonusers. It should be used with cau- tion in patients with impaired liver function and renal function, as well as those with an obstructed bile duct and pancreatic dis- ease. Orlistat is contraindicated in malabsorption syndromes, hypersensitivity to orlistat, reduced gallbladder function, and in pregnancy and breast-feeding. Orlistat is rated pregnancy Category X. Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. Multivitamin supple- ments that contain vitamins A, D, E, K, as well as b -carotene should be taken once a day, preferably at bedtime. Orlistat can reduce plasma levels of the immunosuppressant cyclosporine (Sandimmune), so the two drugs should therefore not be administered concomitantly. Orlistat can also impair absorption of the antiarrhythmic amiodarone (Nexterone). At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30 percent