10 - 29.10 Bupropion

29.10 Bupropion

Conversely, oxazepam has an approximate dosage equivalence of 15 mg and is a lowpotency drug. Zaleplon is available in 5- and 10-mg capsules. A single 10-mg dose is the usual adult dose. The dose can be increased to a maximum of 20 mg as tolerated. A single dose of zaleplon can be expected to provide 4 hours of sleep with minimal residual impairment. For persons older than age 65 years or persons with hepatic impairment, an initial dose of 5 mg is advised. Eszopiclone is available in 1-, 2-, and 3-mg tablets. The starting dose should not exceed 1 mg in patients with severe hepatic impairment or those taking potent CYP3A4 inhibitors. The recommended dosing to improve sleep onset or maintenance is 2 or 3 mg for adult patients (ages 18 to 64 years) and 2 mg for older adult patients (ages 65 years and older). The 1-mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. Table 29.9-1 lists preparations and doses of medications discussed in this chapter. REFERENCES Bahmad FM Jr, Venosa AR, Oliveira CA. Benzodiazepines and GABAergics in treating severe disabling tinnitus of predominantly cochlear origin. Int Tinnitus J. 2006; 12:140. Bannan N, Rooney S, O’Connor J. Zopiclone misuse: An update from Dublin. Drug Alcohol Rev. 2007;26:83. Brands B, Blake J, Marsh DC, Sproule B, Jeypalan R, Li S. The impact of benzodiazepine use on methadone maintenance treatment outcomes. J Addictive Disease. 2008; 27:37. Dubovsky SL. Benzodiazepine receptor agonists and antagonists. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3044. Dell’osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry. 2013;28(1):7–20. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS. Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam. J Clin Psychopharmacol. 2000;20:338. Katsura M. Functional involvement of cerebral diazepam binding inhibitor (DBI) in the establishment of drug dependence. Nippon Yakurigaku Zasshi. 2001;117:159. Korpi ER, Matilla MJ, Wisden W, Luddens H. GABA(A)-receptor subtypes: Clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med. 1997;29:275. Lemmer B. The sleep–wake cycle and sleeping pills. Physiol Behav. 2009;90:285. Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther. 2006;28:490. 29.10 Bupropion Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban) is an antidepressant drug that inhibits the reuptake of norepinephrine and, possibly, dopamine. Most significantly, it does not act on the serotonin system like SSRI antidepressants. This results in a side effect profile characterized by a low risk of sexual dysfunction and

sedation and with modest weight loss during acute and long-term treatment. No withdrawal syndrome has been linked to discontinuation of bupropion. Although increasingly used as first-line monotherapy, a significant percentage of bupropion use occurs as add-on therapy to other antidepressants, usually SSRIs. Bupropion has been marketed under the name Zyban for use in smoking cessation regimens. PHARMACOLOGIC ACTIONS Three formulations of bupropion are available: immediate release (taken three times daily), sustained release (taken twice daily), and extended release (taken once daily). The different versions of the drug contain the same active ingredient but differ in their pharmacokinetics and dosing. There have been reports of inconsistencies in bioequivalence between various branded and generic versions of bupropion. Any changes with this drug in tolerability or clinical efficacy in a patient who had been doing well should prompt an inquiry about whether these changes correspond to a switch to a new formulation. Immediate-release bupropion is well absorbed from the GI tract. Peak plasma concentrations of bupropion are usually reached within 2 hours of oral administration, and peak levels of the sustained-release version are seen after 3 hours. The mean halflife of the compound is 12 hours, ranging from 8 to 40 hours. Peak levels of extendedrelease bupropion occur 5 hours after ingestion. This provides a longer time to maximum plasma concentration (tmax) but comparable peak and trough plasma concentrations. The 24-hour exposure occurring after administration of the extendedrelease version of 300 mg once daily is equivalent to that provided by sustained release of 150 mg twice daily. Clinically, this permits the drug to be taken once a day in the morning. Plasma levels are also reduced in the evening, making it less likely for some patients to experience treatment-related insomnia. The mechanism of action for the antidepressant effects of bupropion is presumed to involve the inhibition of dopamine and norepinephrine reuptake. Bupropion binds to the dopamine transporter in the brain. The effects of bupropion on smoking cessation may be related to its effects on dopamine reward pathways or to inhibition of nicotinic acetylcholine receptors. THERAPEUTIC INDICATIONS Depression Although overshadowed by the SSRIs as first-line treatment for major depression, the therapeutic efficacy of bupropion in depression is well established in both outpatient and inpatient settings. Observed rates of response and remission are comparable to those seen with the SSRIs. Bupropion has been found to prevent seasonal major depressive episodes in patients with a history of seasonal pattern or affective disorder. Smoking Cessation

As the brand name Zyban, bupropion is indicated for use in combination with behavioral modification programs for smoking cessation. It is intended to be used in patients who are highly motivated and who receive some form of structured behavioral support. Bupropion is most effective when combined with nicotine substitutes (NicoDerm, Nicotrol). Bipolar Disorders Bupropion is less likely than tricyclic antidepressants to precipitate mania in persons with bipolar I disorder and less likely than other antidepressants to exacerbate or induce rapid-cycling bipolar II disorder; however, the evidence about use of bupropion in the treatment of patients with bipolar disorder is limited. Attention-Deficit/Hyperactivity Disorder Bupropion is used as a second-line agent, after the sympathomimetics, for treatment of attention-deficit/hyperactivity disorder (ADHD). It has not been compared with proven ADHD medications such as methylphenidate (Ritalin) or atomoxetine (Strattera) for childhood and adult ADHD. Bupropion is an appropriate choice for persons with comorbid ADHD and depression or persons with comorbid ADHD, conduct disorder, or substance abuse. It may also be considered for use in patients who develop tics when treated with psychostimulants. Cocaine Detoxification Bupropion may be associated with a euphoric feeling; thus, it may be contraindicated in persons with histories of substance abuse. However, because of its dopaminergic effects, bupropion has been explored as a treatment to reduce the cravings for cocaine in persons who have withdrawn from the substance. Results have been inconclusive, with some patients showing a reduction in drug craving and others finding their cravings increased. Hypoactive Sexual Desire Disorder Bupropion is often added to drugs such as SSRIs to counteract sexual side effects and may be helpful as a treatment for nondepressed individuals with hypoactive sexual desire disorder. Bupropion may improve sexual arousal, orgasm completion, and sexual satisfaction. PRECAUTIONS AND ADVERSE REACTIONS Headache, insomnia, dry mouth, tremor, and nausea are the most common side effects. Restlessness, agitation, and irritability may also occur. Patients with severe anxiety or panic disorder should not be prescribed bupropion. Most likely because of its potentiating effects on dopaminergic neurotransmission, bupropion can cause psychotic

symptoms, including hallucinations, delusions, and catatonia, as well as delirium. Most notable about bupropion is the absence of significant drug-induced orthostatic hypotension, weight gain, daytime drowsiness, and anticholinergic effects. Some persons, however, may experience dry mouth or constipation and weight loss. Hypertension may occur in some patients, but bupropion causes no other significant cardiovascular or clinical laboratory changes. Bupropion exerts indirect sympathomimetic activity, producing positive inotropic effects in human myocardium, an effect that may reflect catecholamine release. Some patients experience cognitive impairment, most notably word-finding difficulties. Concern about seizure has deterred some physicians from prescribing bupropion. The risk of seizure is dose dependent. Studies show that at dosages of 300 mg a day or less of sustained-release bupropion, the incidence of seizures is 0.05 percent, which is no worse than the incidence of seizures with other antidepressants. The risk of seizures increases to about 0.1 percent with dosages of 400 mg a day. Changes in electroencephalographic (EEG) waveforms have been reported to be associated with bupropion use. About 20 percent of individuals treated with bupropion exhibit spike waves, sharp waves, and focal slowing. The likelihood of women having sharp waves is higher than for men. The presence of these waveforms in individuals taking a medication known to lower the seizure threshold may be a risk factor for developing seizures. Other risk factors for seizures include a history of seizures, use of alcohol, recent benzodiazepine withdrawal, organic brain disease, head trauma, or pretreatment epileptiform discharges on EEG. The use of bupropion by pregnant women is not associated with specific risk of increased rate of birth defects. Bupropion is secreted in breast milk, so the use of bupropion in nursing women should be based on the clinical circumstances of the patient and the judgment of the clinician. Few deaths have been reported after overdoses of bupropion. Poor outcomes are associated with cases of huge doses and mixed-drug overdoses. Seizures occur in about one-third of all overdoses and are dose dependent, with those having seizures ingesting a significantly higher median dose. Fatalities can involve uncontrollable seizures, sinus bradycardia, and cardiac arrest. Symptoms of poisoning most often involve seizures, sinus tachycardia, hypertension, GI symptoms, hallucinations, and agitation. All seizures are typically brief and self-limited. In general, however, bupropion is safer in overdose cases than are other antidepressants except perhaps SSRIs. DRUG INTERACTIONS Given the fact that bupropion is frequently combined with SSRIs or venlafaxine, potential interactions are significant. Bupropion has been found to have an effect on the pharmacokinetics of venlafaxine. One study noted a significant increase in venlafaxine levels and a consequent decrease in its main metabolite O-desmethylvenlafaxine during combined treatment with sustained-release bupropion. Bupropion hydroxylation is weakly inhibited by venlafaxine. No significant changes in plasma levels of the SSRIs

paroxetine and fluoxetine have been reported. However, few case reports indicate that the combination of bupropion and fluoxetine (Prozac) may be associated with panic, delirium, or seizures. Bupropion in combination with lithium (Eskalith) may rarely cause CNS toxicity, including seizures. Because of possibility of inducing a hypertensive crisis, bupropion should not be used concurrently with monoamine oxidase inhibitors (MAOIs). At least 14 days should pass after the discontinuation of an MAOI before initiating treatment with bupropion. In some cases, the addition of bupropion may permit persons taking antiparkinsonian medications to lower the doses of their dopaminergic drugs. However, delirium, psychotic symptoms, and dyskinetic movements may be associated with the coadministration of bupropion and dopaminergic agents such as levodopa (Larodopa), pergolide (Permax), ropinirole (Requip), pramipexole (Mirapex), amantadine (Symmetrel), and bromocriptine (Parlodel). Sinus bradycardia may occur when bupropion is combined with metoprolol. Carbamazepine (Tegretol) may decrease plasma concentrations of bupropion, and bupropion may increase plasma concentrations of valproic acid (Depakene). In vitro biotransformation studies of bupropion have found that formation of a major active metabolite, hydroxybupropion, is mediated by CYP2B6. Bupropion has a significant inhibitory effect on CYP2D6. LABORATORY INTERFERENCES A report has appeared indicating that bupropion may give a false-positive result on urinary amphetamine screens. No other reports have appeared of laboratory interferences clearly associated with bupropion treatment. Clinically nonsignificant changes in the electrocardiogram (premature beats and nonspecific ST-T changes) and decreases in the white blood cell count (by about 10 percent) have been reported in a small number of persons. DOSAGE AND CLINICAL GUIDELINES Immediate-release bupropion is available in 75-, 100-, and 150-mg tablets. Sustainedrelease bupropion is available in 100-, 150-, 200-, and 300-mg tablets. Extended-release bupropion comes in 150- and 300-mg strengths. There have been problems associated with one of the extended-release generic versions called Budeprion XL 300-mg tablets, which was found not to be therapeutically equivalent to Wellbutrin XL 300 mg and was removed from the market. Initiation of immediate-release bupropion in the average adult person should be 75 mg orally twice a day. On the fourth day of treatment, the dosage can be increased to 100 mg three times a day. Because 300 mg is the recommended dose, the person should be maintained on this dose for several weeks before increasing it further. The maximum dosage, 450 mg a day, should be given as 150 mg three times a day. Because of the risk of seizures, increases in dose should never exceed 100 mg in a 3-day period; a single dose of immediate-release bupropion should never exceed 150 mg, and the total daily