Bupropion

Bupropion (INN; also amfebutamone, brand names Wellbutrin and Zyban) is an antidepressant of the aminoketone class, chemically unrelated to tricyclics or selective serotonin reuptake inhibitors (SSRIs). It is similar in structure to the stimulant cathinone, anorectic diethylpropion and to phenethylamines in general. Bupropion is both a dopamine reuptake inhibitor and a norepinephrine reuptake inhibitor. It is used as a smoking cessation aid under the brand name Zyban, and as an antidepressant under the brand name Wellbutrin, Wellbutrin SR and Wellbutrin XL.

Trade names

 * Odranal (Colombia)
 * Quomen (Thailand)
 * Well (Korea)
 * Zyban LP (France)
 * Zyban Sustained Release (Australia)
 * Zyban SR (United Kingdom)

History
Bupropion was first synthesized by Burroughs Research in 1966, and patented by Burroughs-Wellcome (later Glaxo-Wellcome, and, as of 2000, GlaxoSmithKline) in 1974. It was approved by the Food and Drug Administration (FDA) as an antidepressant in 1984 and marketed under the name Wellbutrin. However, a significant incidence of seizures at the originally recommended dosage (400-600 mg) caused in 1986 the removal of the drug from the market. It was shown that the risk of seizures increases from 0.1% at 100-300 mg/day to 0.3-0.4% at 450 mg/day to 2% at 600 mg/day. Reflecting this experience, bupropion was re-introduced to the market in 1989 with the maximum dose of 450 mg/day.

In 1996 the FDA approved sustained-release (SR) and in 2003 extended release (XL) formulations of Wellbutrin that release bupropion at a slower rate. Wellbutrin SR is taken twice a day and Wellbutrin XL once a day, as compared to three times a day for the immediate release bupropion. Wellbutrin SR and XL are now available in generic form as Budeprion SR and XL.

In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In late 2006, Wellbutrin XL was approved for use by the FDA as treatment for seasonal affective disorder.

Indications
Bupropion's main use is for smoking cessation. It reduces the severity of nicotine cravings and addiction/withdrawal symptoms. Bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco around ten days into the course. The efficacy of bupropion is similar to that of nicotine replacement therapy. Bupropion approximately doubles the chance of quitting smoking successfully after 3 months. After 1 year the odds of sustaining smoking cessation are 1.5 higher for bupropion than for placebo. Combination of bupropion and nicotine appears not to further increase the cessation rate. In a direct comparison, recently approved varenicline showed superior efficacy. After 1 year the rate of continuous abstinency was 10% for placebo, 15% for bupropion, and 23% for varenicline.

Bupropion is also approved for use in major depression and seasonal affective disorder. Bupropion has been investigated for several other disorders including obesity, attention-deficit hyperactivity disorder, restless legs syndrome and antidepressant-caused sexual dysfunction.

Mode of action
Bupropion is a dopamine and norepinephrine reuptake inhibitor. It is about twice as potent inhibitor of dopamine uptake than norepinephrine uptake. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without understanding its metabolism. Occupancy of dopamine transporter (DAT) by bupropion and its metabolites in human brain measured by positron emission tomography was 6–22% according to an independent study and 12–35% according to GSK researchers. Based on the analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of bupropion action. Bupropion does not inhibit MAO (i.e. is not a MAOI) and serotonin reuptake. However, it has been shown to indirectly enhance firing of serotonergic neurons (via activation of downstream norepinephrine flow). Bupropion has also been shown to act as a noncompetitive α3β4 nicotinic antagonist. The degree of inhibition of α3β4-receptors correlates well with the decrease of self-administration of morphine and metamphetamine in rats, and may be relevant to the effect of bupropion on nicotine addiction.

Pharmacokinetics
Bupropion is metabolized in the liver. It has at least three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. These active metabolites are further metabolized to inactive metabolites and eliminated through excretion into the urine. The half-life of bupropion is 20 hours, as is hydroxybupropion's. Threohydrobupropion's half-life is 37 hours and erythrohydrobupropion's is 33 hours. The therapeutic benefit of bupropion can be attributed to its active metabolites to a much greater degree than bupropion in its plain form. Significant interspecies differences in metabolism of bupropion exist, with guinea pigs' metabolism of the drug being closest to the human metabolism. Particular caution is needed when extrapolating the results of the experiments on rats to humans since hydroxybupropion, the main metabolite of bupropion in humans, is absent in rats.

Hydroxybupropion is being exploited in the development of Radafaxine, a drug in development by GSK.

Chronic hepatotoxicity in animals
In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.

Contraindications

 * Epilepsy and other conditions that lower the seizure threshold (alcohol withdrawal, active brain tumors, etc.)
 * Concomitant treatment with MAO inhibitors. When switching medications it is important that there be a short period of about two weeks between the medications in order to reduce risk of complications that might lead to things such as a decrease in seizure threshold.
 * Caution with the concomitant use of sympathomimetic drugs (e.g. ephedrine)
 * Active liver damage (e.g. cirrhosis)
 * Anorexia nervosa and bulimia which might lead the patient to have a decreased seizure threshold
 * Severe kidney disease
 * Severe hypertension
 * Anxiety disorders (caution), agitated patients
 * Pediatric patients (see below)
 * Use considerable caution in treating patients where suicide may be a risk
 * Psychosis, as bupropion therapy has a record of worsening and sometimes causing hallucinations, paranoia, and feelings of persecution.

Side effects
Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, dizziness, hypertension, headache, excessive sweating such as night sweats, increased risk of seizure (its most controversial side effect, found in 4/1000 during trials), aggressiveness, tinnitus, and both initial and terminal insomnia. Activation of mania and psychosis have both been encountered. The side effect profile is consistent with that observed in mixed dopamine and norepinephrine reuptake inhibition. Some patients may also require less than the normal dosing which usually starts at around 75 mg for the first few weeks and is then switched to the normal 150–300 mg dosage; these patients may be kept on the 150 mg regimen however, some patients are experimentally placed on doses as high and sometimes exceeding, 600 mg/day. Dosage is strictly on a patient to patient basis and can vary greatly.

Although with the recommended dosing incidence of seizures is comparable to, and in some cases lower than, that of other antidepressants, patients using Bupropion should still be screened for pre-disposing factors that could contribute to and/or indicate a low seizure threshold. A prescriber may also review all other medications/substances the patient might be using and make dosing decisions based on the results.

Suicidal thoughts and attempts have been reported in children and adolescents.

Another potential side effect is an improvement in sexual function. Bupropion, unlike SSRIs, does not appear to reduce libido, and more frequently enhances sexual functioning. Patients who complain of sexual dysfunction as a result of their SSRI have sometimes been prescribed small doses of bupropion, amphetamine or methylphenidate to correct it.

Scattered abnormalities of liver function tests are noted, without evidence of hepatotoxicity. Cases of significant liver damage with or without jaundice (icterus) have been seen rarely. In a German database covering side effects, five cases of pancreatitis with elevations of serum-amylase and lipase as well as clinical symptoms (e.g. abdominal pain, anorexia), reversible after termination of bupropion, have been reported. Currently, it is unclear whether preexisting alcohol abuse or dependence might predispose patients to develop pancreatitis.

Infrequently, dose-dependent hypertension is noted. Single cases of myocardial infarction (heart attack) have been noted, but the causal association to the use of bupropion is currently unknown.

The development of mild to moderate skin rashes associated with sensitivity to dye components within the pill coating. This can often be alleviated by simply prescribing a different color pill and consequently, changing the dosage.

Few cases of the urological emergency priapism (painful erection) have been seen. Immediate treatment is necessary, because the untreated patient may totally lose his ability to have erections.

Interactions
Quite a great number of drugs show clinically significant interactions with bupropion. This may be due to interactions with drugs that are metabolized by CYP2D6 as bupropion inhibits CYP2D6 activity. However, bupropion is not metabolized by CYP2D6.

Manufacturer studies have also indicated that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Theoretically, drug interactions could occur between bupropion and substrates or inhibitors of CYP2B6 (e.g. orphenadrine, thiotepa, or cyclophosphamide).

Bupropion is known to lower the seizure threshold. Bupropion, in combination with other medications, has been suspected to induce seizures in some patients with no prior record of seizure activity. While this is not a common side-effect, a growing number of cases world wide validate the need for consideration. It is not uncommon for patients to receive treatment with other antidepressant and/or atypical antipsychotic medications in combination with bupropion. For this reason, care should be taken when prescribing bupropion with other medications prone to lower the seizure threshold. Bupropion has also been known to produce seizures in combination with non-prescription (recreational) drugs such as cocaine and alcohol.

Combination with nicotine replacement therapies can elevate blood pressure, so it is recommended that the patient's blood pressure is monitored.

Abuse liability
In animal studies and small studies with persons having experience with the use of amphetamines or cocaine, bupropion caused drug-seeking behaviour (animal experiments) and was recognized as an amphetamine-like drug by humans. Dopamine reuptake inhibition is responsible for the euphoria promoted by Cocaine, and Norepinephrine reuptake inhibition is responsible for the energizing effects of Cocaine. Because of this, there has been concern and controversy regarding the abuse liability of bupropion. In a scale ranging from placebo on the lower side to amphetamine, it was given an intermediate score indicating moderate likelihood of abuse. The stimulant effect reliably produced in mice however, has not been reliably seen in humans. There are isolated reports of patients crushing and insufflating bupropion and increasing dosages to attain a cocaine-like stimulant effect; however this often results in seizures and other severe side effects. In clinical practice, bupropion has been shown that the dose required for significant abuse would cause seizures in most patients. Bupropion is the only dopamine reuptake inhibitor/enhancer not classified as a scheduled stimulant, since reliable euphoria is not produced by the drug in doses that do not commonly induce seizures. While abuse has not become a significant problem in clinical usage, the drug should be given with caution to patients with a history of drug or alcohol abuse or dependence.

Dosage

 * Depression: the target dosage is 300 mg daily, starting with 150 mg in the first few days. If indicated and directed by physician, the dosage may be increased to a maximum of 450 mg daily.
 * Tobacco withdrawal: 150 mg initially, may be increased to 300 mg if indicated and directed by physician. In patients also receiving insulin, sympathomimetic anorectical drugs, or antimalaria agents, the daily dose of bupropion should not exceed 150 mg.

Dose forms
Brand and generic pills are available in three forms: immediate release, sustained release (SR), and extended release (XL, ER).

Overdosage
GlaxoSmithKline has reported that overdoses of up to 30 g or more of Wellbutrin (bupropion) had resulted in seizure in about one third of all cases. Hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias were reported as other serious reactions of overdoses of bupropion alone. Multiple overdoses including bupropion had resulted in fever, rhabdomyolysis, stupor, hypotension, coma, muscle rigidity, and respiratory failure.

May cause false-positive for amphetamine
Bupropion contains a similar pharmacological structure to that of amphetamines. In most cases prescription medications that contain bupropion (Wellbutrin, Zyban) will cause urinary drug tests to read a positive result in both amphetamines and occasionaly, methamphetamine categories. It is imperative that the patient receiving bupropion treatment inform any administrators and interpreters of drug use tests of this.

Use in pediatric patients
Bupropion has been shown to increase the incidence of suicidal thoughts and attempts in children and adolescents with depression. When treating major depressive disorder in this group of patients, clinical benefits should be weighed carefully against therapeutic hazards. Usually, bupropion is not indicated for pediatric patients under age 18.

Potential indications of bipolar and schizoaffective disorder
The effects of bupropion in treating eleven patients with bipolar or schizoaffective disorder were examined in an open trial. Most patients had been intolerant of or showed minimal to moderate improvement on lithium, neuroleptics, antidepressants, or a combination of these drugs. All patients were maintained on bupropion alone or bupropion in combination with low-dose neuroleptics or anxiolytics for one year or more, with little or no relapse and few side effects. Although these results are encouraging, additional larger studies need to be conducted to confirm this indication.

Alleged risks with certain treatments
In the UK, more than 7,000 reports of potential hazardous side effects have been collected. There have been 44 reports of suspected adverse reactions where there was a fatal outcome while taking Zyban. In reviewing these cases the MHRA stated that in the majority of cases the individual’s underlying condition may provide an alternative explanation. More than two thirds of reported deaths were from cardio-vascular or cerebro-vascular causes. A case-series analysis showed increased risk of seizure in the population taking bupropion, but no increase in the risk of sudden death. At least 107 cases of serious side effects have been reported in Germany.

In the UK, bupropion should only be prescribed as an aid in quitting smoking to smokers who have committed to a definite quit date and a prescription will not last more than 4 weeks after this target date. NICE has issued guidance to the effect that if the attempt to quit is unsuccessful the NHS will not provide funding for a further course, for at least 6 months.

In some countries, such as the UK, bupropion is approved only as a smoking cessation aid and not for treatment of depression.

Studies of juveniles with depression
A large study gathered the results of twenty-four studies of juveniles with depression. Patients were to take either a placebo (sugar pill) or an antidepressant (SSRIs and others, including bupropion) for one to four months. According to the results, nobody committed suicide in these studies, although two out of every hundred patients became suicidal on a placebo and four out of every hundred become suicidal on antidepressants. Results indicated that the risks of suicidal actions become high for some juveniles. These kinds of juveniles may include patients with:
 * Bipolar illness, previously known as manic-depressive illness
 * A family history of bipolar illness
 * A personal or family history of attempting or committing suicide