Major Depressive Disorder
Bupropion hydrochloride is used in the treatment of major depressive disorder. Efficacy of conventional bupropion tablets for long-term use (i.e., exceeding 6 weeks) as an antidepressant has not been established by controlled studies; if conventional or extended-release tablets of the drug are used for extended periods, the need for continued therapy should be reassessed periodically. Systematic evaluation of bupropion hydrochloride extended-release tablets has shown that antidepressant efficacy is maintained for periods of up to 44 weeks in patients receiving 150 mg twice daily.
Efficacy of bupropion for the management of major depression has been established by a controlled study of approximately 6 weeks' duration in an outpatient setting and by 2 controlled studies of approximately 4 weeks' duration in inpatient settings. Bupropion hydrochloride was administered as conventional tablets in these studies, and the dosage received by 78% of the patients in one of the studies of 4 week's duration was 450 mg or less daily, although the dosage was titratable to 600 mg daily. Efficacy of bupropion in these studies was demonstrated by improvement in total score on the Hamilton rating scale for depression (HAM-D), in item 1 of the HAM-D that measures depressed mood, and in the Clinical Global Impressions of Severity of Illness (CGI-S) scale. Patients received 300 or 450 mg daily of bupropion hydrochloride in the second study of 4 weeks' duration, which demonstrated efficacy only of the higher dosage, as indicated by improvement in total score on the HAM-D and in the CGI-S scale. However, in the study of 6 weeks' duration that evaluated the efficacy of 300 mg daily of bupropion hydrochloride, the drug was superior to placebo in improvement of total score on the HAM-D, which was the primary measure of efficacy. In addition, depressed mood, as measured by item 1 on the HAM-D, was improved in patients treated with bupropion. The drug also was superior to placebo in improvement of scores on the Montgomery-Asberg Depression Rating Scale, the CGI-S scale, and the Clinical Global Impressions of Improvement (CGI-I) scale. Although clinical studies specifically establishing the efficacy of extended-release tablets of bupropion in the management of major depression have not been performed to date, the extended-release, film-coated tablet (e.g., Wellbutrin SR) formulation of the drug has been shown to be bioequivalent at steady state to conventional tablets of bupropion, and antidepressant efficacy was maintained for up to 44 weeks in a placebo-controlled study. In addition, the extended-release tablet (Wellbutrin XL) has been shown to be bioequivalent to the conventional and the extended-release, film-coated tablets.
(See Pharmacokinetics: Absorption.)
A major depressive episode is characterized principally by a relatively persistent depressed mood and/or loss of interest or pleasure in all or almost all activities; such symptoms differ from previous functioning and occur for most of the day nearly every day for at least 2 weeks. In addition, the episode may be manifested as a change in appetite, substantial weight loss or gain, a change in sleep, psychomotor agitation or retardation, fatigue or loss of energy, feelings of guilt or worthlessness, difficulty in thinking or concentrating, and/or suicidal ideation or attempts.
Clinical studies have shown that the antidepressant effect of usual dosages of bupropion in patients with moderate to severe depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants, fluoxetine, or trazodone. Bupropion generally was not distinguishable from these antidepressant agents in measures of efficacy that included the HAM-D scale, the CGI-S scale, the CGI-I scale, and the Hamilton rating scale for anxiety (HAM-A). However, other antidepressants were associated with greater improvement on the HAM-D rating scale during some weeks of the evaluations principally because of the greater improvement in the sleep factor of this scale observed with tricyclic antidepressants or trazodone in comparison to bupropion.
Because of differences in the adverse effect profile between bupropion and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, antihistaminic effects, and weight gain with bupropion therapy, bupropion may be preferred for patients in whom such effects are not tolerated or are of potential concern. In a study that compared bupropion with doxepin, discontinuance of therapy because of adverse effects resulted mainly from anticholinergic effects, particularly drowsiness, in patients treated with doxepin but from a variety of adverse effects in patients treated with bupropion. After 13 weeks of therapy, patients who received doxepin had gained 2.73 kg while those who received bupropion had lost 1.36 kg. Orthostatic hypotension that required discontinuance of the antidepressant agent occurred with some frequency with imipramine but not with bupropion. In addition, in a large open study, 54% of patients who responded poorly to previous antidepressant therapy responded to bupropion therapy, and 63% of patients who poorly tolerated previous antidepressant therapy tolerated bupropion; 81% of patients who completed an initial 8-week treatment phase in this study elected to receive maintenance therapy with bupropion. Although the possibility of bupropion-induced seizures should be considered in weighing the benefits versus risks compared with alternative therapies, the risk of seizures appears to be within clinically acceptable parameters in patients without preexisting risk.
(See Cautions: Nervous System Effects.)
Bupropion also may be preferable because of its minimal adverse effects and possibly beneficial effects on sexual functioning. Most men with depression who experienced sexual dysfunction (e.g., decreased libido, partial erectile failure) during therapy with another antidepressant (e.g., tricyclic antidepressant, maprotiline, trazodone, tranylcypromine) did not have such impairment with bupropion. In a study comparing the adverse sexual effects of bupropion with those of selective serotonin-reuptake inhibitors (i.e., fluoxetine, paroxetine, and sertraline), statistically significant increases in libido, sexual arousal, intensity of orgasm, and/or duration of orgasm were reported in most bupropion-treated patients compared with those reported before the onset of illness, while selective serotonin-reuptake inhibitor therapy significantly reduced these aspects of sexual functioning in most of the patients studied. In another study, dysfunctional orgasm resolved when antidepressant therapy was changed from fluoxetine to bupropion in most men and women who developed orgasm failure and/or delay with fluoxetine. Libido and satisfaction with overall sexual functioning also were improved with bupropion. Limited experience suggests that bupropion also may be useful in the management of sexual dysfunction associated with fluoxetine. Sexual dysfunction (e.g., decreased libido, erectile and orgasmic impairment) associated with fluoxetine was reported to respond to concomitant administration of 75 mg daily of bupropion hydrochloride.
Bupropion administered alone or concurrently with other antidepressant agents may be useful in patients with refractory depression. In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram, a selective serotonin-reuptake inhibitor (SSRI), were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline (another SSRI), or extended-release venlafaxine (a selective serotonin- and norepinephrine-reuptake inhibitor) as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26%, 27%, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant, and either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.
In a second STAR*D level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate SSRI therapy (citalopram) were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale, effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.
For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, .
Seasonal Affective Disorder
Bupropion, as extended-release tablets (Wellbutrin XL), is used in the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD; also referred to as winter depression). Seasonal affective disorder is characterized by recurrent major depressive episodes, most commonly occurring during the autumn and/or winter months. Episodes may last up to 6 months and typically begin in the autumn and remit in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the number of seasonal episodes should substantially outnumber the number of nonseasonal episodes during the individual's lifetime for a diagnosis of seasonal affective disorder to be considered.
Efficacy of bupropion, as extended-release tablets, for the prevention of seasonal major depressive episodes associated with seasonal affective disorder has been established in 3 double-blind, placebo-controlled trials in adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Bupropion therapy was initiated prior to symptom onset during the autumn (September to November), continued through the winter months, and discontinued following a 2-week tapering period beginning the first week of spring (the fourth week of March), which resulted in a treatment duration of approximately 4 to 6 months for the majority of patients. Patients were randomized to receive either placebo or 150 mg of bupropion as extended-release tablets (Wellbutrin XL) once daily for 1 week, then the dosage was titrated upward to 300 mg once daily. Patients judged by the investigator to be unlikely or unable to tolerate the 300-mg daily dosage were allowed to continue to receive 150 mg daily or to have their dosage reduced to 150 mg once daily; mean dosages in the 3 studies ranged from 257-280 mg once daily. In these 3 trials, a substantially higher percentage of patients receiving bupropion extended-release tablets were depression-free at the end of treatment compared with those receiving placebo (81.4 vs 69.7%, 87.2 vs 78.7%, and 84 vs 69%, respectively, for studies 1, 2, and 3, respectively); the depression-free rate for the 3 studies combined was 84.3% for extended-release bupropion tablets and 72% for placebo.
Bupropion, as extended-release tablets, is used as an adjunct in the cessation of smoking. Such therapy may be combined with nicotine replacement therapy if necessary. However, the manufacturer states that before patients receive this combination of therapies, the labeling for both bupropion and nicotine should be consulted and recommends that patients who receive bupropion and nicotine concurrently be monitored for the development of hypertension related to such therapy.
(See Cautions: Cardiovascular Effects.)
The US Public Health Service (USPHS) guideline for the treatment of tobacco use and dependence recommends bupropion (as extended-release tablets) as one of several first-line drugs that may reliably increase long-term smoking abstinence rates. Nicotine (tobacco) dependence is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention. Because effective nicotine dependence therapies are available, every patient should be offered effective treatment, and those who are unwilling to attempt cessation should be provided at least brief interventions designed to increase their motivation to stop tobacco use. Delineated in the current USPHS guideline for the treatment of tobacco use and dependence are 5 brief strategies of intervention that can be provided by any clinician; these strategies consist of asking patients if they use tobacco, advising those who use tobacco to quit, assessing their willingness to quit, assisting those who attempt to quit, and arranging follow-up to prevent relapse. Also included in the USPHS guideline are recommendations for the use of pharmacotherapy in general, first-line drugs (i.e., extended-release bupropion, buccal [gum or lozenge] nicotine polacrilex, transdermal nicotine, nicotine nasal spray, nicotine oral inhaler, varenicline) that should be considered initially as part of treatment for tobacco dependence, unless contraindicated, and second-line drugs (i.e., clonidine, nortriptyline). Clinicians should encourage all patients attempting to quit smoking to use effective pharmacotherapy, except when contraindicated or in specific populations for which there is insufficient evidence of efficacy (e.g., pregnant women, smokeless tobacco users, light smokers [e.g., less than 10 cigarettes daily], adolescents). For additional information on smoking cessation, , and also consult the most current USPHS Clinical Practice Guideline on Treating Tobacco Use and Dependence available at http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/index.html.
Bupropion (extended-release) may be particularly useful in patients greatly concerned about gaining weight after cessation of smoking since therapy with the drug has been shown to result in delay in such gain in weight. Nicotine dependence therapy with an antidepressant such as bupropion also may be particularly useful when a depressive disorder is included in the current or past history of patients attempting to quit smoking. Although it is not necessary to assess for possible comorbid psychiatric disorders prior to initiating therapy for nicotine dependence, awareness of such comorbidity is important in the assessment and treatment of nicotine-dependent patients since psychiatric disorders are common in this population, smoking cessation or nicotine withdrawal may exacerbate the comorbid condition, bupropion and varenicline therapy have been associated with worsening of preexisting psychiatric disorders in some cases, and patients with psychiatric comorbidities have an increased risk for relapse to smoking after a cessation attempt.
It should be considered that serious neuropsychiatric adverse effects (including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide) have been reported during postmarketing experience in patients being treated with bupropion or varenicline (another smoking cessation drug).
(See Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment under Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.)The possible risk of serious adverse effects during bupropion therapy should always be weighed against the significant health benefits of its use for smoking cessation, including a reduction in the risk of developing pulmonary disease, cardiovascular disease, and cancer.
Patients should begin receiving bupropion while they are still smoking since steady-state plasma concentrations of the drug are not achieved until after about 1 week. A date on which patients quit smoking (cessation date) should be scheduled within the first 2 weeks of therapy with bupropion and generally should be set for the second week (e.g., day 8). Counseling and support are important interventions for patients to receive throughout therapy with bupropion and for a period after its discontinuance. Achievement of cessation of smoking and maintenance of abstinence are more likely with frequent follow-ups and the provision of support by the clinician and other health-care professionals. The importance of participation in behavioral therapies, counseling, and/or support services to which bupropion is adjunctive therapy should be discussed with the patient. The overall program of interventions to enable cessation of smoking should be reviewed by clinicians. The choice of adjunctive therapy (e.g., nicotine replacement, bupropion) should consider factors such as ease of administration, compliance, and potential adverse effects and risks.
The efficacy of bupropion, as extended-release tablets, as an adjunct in the cessation of smoking has been established in controlled studies of smokers of at least 15 cigarettes daily, who did not have an underlying depressive disorder. Patients were treated with bupropion in conjunction with individual counseling. Cessation of smoking was defined as total abstinence, as determined with patients' daily diaries and verified by measurement of expiratory carbon monoxide, during the fourth through seventh week of treatment. Treatment over 7 weeks with bupropion or placebo resulted in 1-year cessation of smoking in a greater proportion of patients treated with the drug at a dosage of 150 or 300 mg daily but not in those receiving 100 mg daily. Cessation of smoking was achieved at the end of 7 weeks of treatment in 36-44, 27-39, or 17-19% of patients who received 300 mg daily of bupropion hydrochloride, 150 mg daily of the drug, or placebo, respectively. Maintenance of abstinence was observed with bupropion hydrochloride at a dosage of 300 mg daily. At follow-up during the twelfth week, abstinence continued in 25-30 or 14% of patients who had received bupropion hydrochloride at 300 mg daily or placebo, respectively, and at follow-up during the twenty-sixth week, abstinence continued in 19-27 or 11-16% of patients who had received bupropion hydrochloride at 300 mg daily or placebo, respectively.
Treatment over 9 weeks with bupropion at a dosage of 300 mg daily, transdermal nicotine at a dosage of 21 mg/24 hours, the combination of 300 mg daily of bupropion and transdermal nicotine at 21 mg/24 hours, or placebo resulted in cessation of smoking in a greater proportion of patients treated with bupropion, transdermal nicotine, or the combination of bupropion and transdermal nicotine than in those receiving placebo. Cessation of smoking was achieved during weeks 4-7 in 49, 36, 58, or 23% of patients who received bupropion, transdermal nicotine, the combination of bupropion and transdermal nicotine, or placebo, respectively. At follow-up during the tenth week, abstinence was observed in 46, 32, 51, or 20% of patients who had received bupropion, transdermal nicotine, the combination of bupropion and transdermal nicotine, or placebo, respectively. Additionally, when these patients were assessed at 26 weeks, cessation of smoking continued to be observed in 30, 33, and 13% of patients who received bupropion, the combination of bupropion and transdermal nicotine, or placebo, respectively. A final assessment was performed at 52 weeks and abstinence continued to be observed in 23, 28, and 8% of patients who received bupropion, the combination of bupropion and nicotine, or placebo, respectively. The manufacturer states that because the comparisons between bupropion extended-release tablets, transdermal nicotine, or the combination of these products have not been replicated, these data should not be interpreted as demonstrating superiority of any individual treatment protocol.
Another clinical study also reviewed long-term maintenance treatment with bupropion. Patients received bupropion hydrochloride extended-release tablets at a dosage of 300 mg daily for 7 weeks; therapy was continued in the patients who achieved cessation of smoking at 7 weeks with either bupropion hydrochloride extended-release tablets or placebo. At 6-month follow-up, abstinence continued in 55% of patients receiving bupropion compared with 44% of patients who received placebo therapy.
The safety and efficacy of bupropion extended-release tablets as an adjunct in the cessation of smoking in patients with chronic obstructive pulmonary disease (COPD) was established in a clinical trial in adults with mild to moderate COPD (FEV1 at least 35%, FEV1/FVC 70% or less, and a diagnosis of chronic bronchitis, emphysema, and/or small airways disease). Treatment over a 12 week period with bupropion or placebo resulted in cessation of smoking during the final four weeks of the study in 22 or 12% of patients, respectively.
Since efficacy in clinical studies is influenced by the population selected, a lower rate of cessation of smoking is possible with use of bupropion in an unselected population. The reported cessation rates in patients receiving bupropion were similar in patients who had and had not previously received nicotine replacement therapy for the cessation of smoking. Withdrawal symptoms, especially irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, and depressed mood or negative affect, were reduced with bupropion compared with placebo. Craving for cigarettes or urge to smoke appeared to be reduced with bupropion in comparison with placebo.
Bupropion has been used for the treatment of bipolar depression (bipolar disorder, depressive episode). Lithium preferably or lamotrigine alternatively are considered first-line agents by the American Psychiatric Association (APA) for the treatment of acute depressive episode of bipolar disorder, and lamotrigine (if not used initially), bupropion, or paroxetine are considered second-line agents when first-line agents are ineffective or not tolerated. If bupropion was effective for the management of an acute depressive episode, including during the continuation phase, then maintenance therapy with the drug should be considered to prevent recurrences of major depressive episodes. In a comparative study, bupropion (mean dosage of 358 mg daily) was as effective as desipramine (mean dosage of 140 mg daily) in the management of depression in patients with bipolar disorder. Hypomania or mania occurred less frequently with bupropion than with desipramine in patients treated for up to 1 year with either drug and concomitant lithium, carbamazepine, or valproate sodium.
Because bupropion may be less likely than some other antidepressants to cause a switch to mania or rapid cycling in patients with bipolar disorder, many experts consider bupropion a preferred antidepressant for use in combination with a mood-stabilizing agent in patients with severe (nonpsychotic) depression that is unresponsive to therapy with mood-stabilizing agents alone. However, the possibility that manic attacks may be precipitated in patients with bipolar disorder who receive bupropion still must be considered. To reduce the risk of developing mania, antidepressants should not be used alone in patients with depression associated with bipolar disorder and the lowest effective dosage of the antidepressant should be used for the shortest time necessary.
For further information on the management of bipolar disorder,
Attention Deficit Hyperactivity Disorder
Bupropion has been used in a limited number of children with attention deficit hyperactivity disorder (ADHD). Although stimulants (e.g., methylphenidate, dextroamphetamine) usually are considered the drugs of first choice when pharmacotherapy is indicated as an adjunct to psychological, educational, social, and other remedial measures in the treatment of ADHD in children, some clinicians recommend use of bupropion or tricyclic antidepressants as second-line therapy when there has been no response to at least 2 stimulants or when the patient is intolerant of stimulants. In controlled studies, bupropion was more effective than placebo and comparably effective to methylphenidate. In addition, in a comparative study, bupropion hydrochloride (mean dosage of 3.3 mg/kg daily; range: 1.4-5.7 mg/kg daily) was comparably effective to methylphenidate hydrochloride (mean dosage of 31 mg daily; range: 20-60 mg daily) in overall improvement of symptoms, as evaluated with the Iowa-Conners Abbreviated Parent and Teacher Questionnaire, although a trend favoring methylphenidate was noted in almost all rating scales.
Bupropion also has been used in a limited number of adults with ADHD. In an uncontrolled study in adults, bupropion (mean dosage of 359 mg daily; range: 150-450 mg daily) administered for 6-8 weeks reduced the severity of signs and symptoms of attention deficit hyperactivity disorder, as evaluated with the Targeted Attention Deficit Disorder Symptoms Scale. Additional study and experience are needed to establish the role of antidepressants versus CNS stimulants in the treatment of this disorder.
For further information on management of ADHD,
Bupropion does not appear to be effective in the treatment of panic disorder and concomitant phobic disorder. However, the drug generally improves symptoms of panic and depression in patients with major depression who have superimposed panic symptoms.
Although bupropion has been used effectively in some patients with bulimia nervosa, the American Psychiatric Association (APA) states that the drug has been associated with seizures in purging bulimic patients and cautions against its use in the management of this disorder. For information on the use of antidepressants in the treatment of bulimia nervosa and other eating disorders, .