Janimine

Bupropion: New Therapy for Depression Approximately one person in five suffers an episode of clinically significant depression at some time during his or her life. Depression remains untreated in many patients, but others consult their family physicians. Family physicians write most of the prescriptions for antidepressant drugs in the United States. [1] The tricyclic antidepressants are considered to be the first-line drugs for the treatment of depression. These drugs, however, are potentially lethal when ingested as an overdose. They also cause many disturbing side effects. Thus, safe and effective antidepressants with fewer side effects and a lower risk of serious consequences from an overdose are needed.

Under intensive investigation for over 20 years, bupropion (Wellbutrin) has recently been approved by the Food and Drug Administration for the treatment of depression. [2,3] Bupropion was initially approved by the FDA for release in 1985. However, after reports of an increased rate of seizures among bulimic patients receiving bupropion, the manufacturer decided not to release the drug until further studies could be performed.

Pharmacodynamics

Bupropion is unique among antidepressant drugs. Its chemical structure is entirely different from tricyclic antidepressants, such as amitriptyline (Amitril, Elavil, Endep, etc.) and imipramine (Janimine, Tofranil, etc.), and from monoamine oxidase (MAO) inhibitors, such as isocarboxazid (Marplan) and phenelzine (Nardil). Bupropion is a monocyclic compound with the same basic structure as phenylethylamine, a sympathomimetic amine. However, substitution of a ketone in the chain and a chloride in the benzene ring removes all potential sympathetic agonist activity. [4]

Antidepressant drugs are thought to exert their therapeutic action through effects on noradrenergic or serotoninergic neural transmission in the brain. The tricyclic antidepressants, such as imipramine and desipramine (Norpramin, Pertofrane), block the reuptake of norepinephrine and/or serotonin by presynaptic neurons. MAO inhibitors block the intraneuronal destruction of these neurotransmitters by binding irreversibly to MAO. New drugs such as fluoxetine (Prozac) only block serotonin reuptake.

The reuptake blockade hypothesis of antidepressant action has several weaknesses, including the fact that drugs acting only on norepinephrine reuptake (e.g., desipramine) and those acting only on serotonin reuptake (e.g., fluoxetine) may be equally effective in the same patient. This phenomenon has led to the development of alternative hypotheses for drug action, including postsynaptic effects such as down-regulation of beta-adrenergic receptors. Antidepressants that act on norepinephrine or serotonin reuptake in presynaptic neurons share this postsynaptic effect. [5]

Bupropion, unlike other antidepressant drugs, has no effect on noradrenergic or serotoninergic transmission and does not block MAO in the brain. [4,6] Although bupropion weakly inhibits dopamine reuptake, this characteristics probably does not explain its action. Nor is bupropion's action thought to result from down-regulation of postsynaptic beta-receptors. [5] Bupropion does not have clinically significant anticholinergic effects and does not seem to block acetylcholine receptors. [5,7] Thus, bupropion's clinical effectiveness as an antidepressant cannot be explained by the present concepts of antidepressant drug action. Perhaps, bupropion produces an active metabolite that has not yet been detected. The dopaminergic effects of the drug undoubtedly contribute to adverse reactions of the central nervous system, such as agitation and psychosis. [4,8,9]

Pharmacokinetics

Peak bupropion levels occur about two hours after an oral dose. Distribution into tissues is rapid; elimination is slow. The drug's half-life is about 12 hours. [10] Administration in three equal doses is the most satisfactory regimen.

Bupropion undergoes extensive biotransformation. Consequently, bioavailability is low. Excretion is mainly by the kidneys, with only 0.5 percent recovery of unchanged drug. Several of the metabolites are active, but they have not yet been fully characterized. Accumulation of active metabolites may be significantly increased in patients with hepatic impairment. A reduced dosage is advised in patients with cirrhosis, since the levels of toxic metabolites in these patients may be two to three times higher than those in healthy persons. [2,10]

Clinical Trials

Bupropion has been evaluated in several large placebo-controlled clinical trials. In several inpatient studies, [11-13] the drug was shown to be superior to placebo at dosages of 450 mg per day or greater. The results of controlled studies in outpatients were less impressive. [13] This may reflect several important differences between the inpatient and outpatient studies. The inpatients were more depressed and had a lower rate of response to placebo than did the less seriously depressed outpatients. In the outpatients study, the high-dose (600 mg per day) treatment group was discontinued because unspecified side effects led to a high dropout rate. [14] In only one published outpatient study has bupropion been superior to placebo at daily dosages of 450 mg or less. [15]

Bupropion was also compared with doxepin (Adapin, Sinequan) in one blinded study. [16] While the drugs were similar in efficacy for depression, doxepin was more effective for insomnia. In another blinded study, [17] bupropion was found to be as effective as amitriptyline.

Adverse Effects

Bupropion has fewer side effects and is generally better tolerated than the tricyclic antidepressants. It is less likely than amitriptyline to cause orthostatic hypotension, increased heart rate or changes in cardiac conduction. [18,19]

Bupropion can produce agitation, insomnia and anxiety, necessitating dosage reduction or drug withdrawal. It also has been associated with major motor seizures at doses in the range of those used for the treatment of depression. [3,10,20,21] This side effect has been noted more frequently in patients with bulimia (four of 69 patients), but seizures also occurred in eight (0.3 percent) of 3,000 depressed patients with no predisposing factors. [3] In several review articles, the incidence of seizures in patients taking bupropion was compared with that in patients taking other antidepressants. [20,21] The data suggest that the incidence of seizures is lower with tricyclic antidepressants than with bupropion. The incidence of seizures in patients taking bupropion is comparable to that in patients taking maprotiline (Ludiomil), another relatively new antidepressants drug. [22]

Animal data suggest that bupropion may interact with certain drugs, such as carbamazepine (Tegretol), cimetidine (Tagamet), phenobarbital and phenytoin (Dilantin), because of indication of liver enzymes. Human data show interaction with levodopa (Dopar, Larodopa) and MAO inhibitors. Drug interactions tend to increase the incidence of toxic effects such as seizures.

Dosage

Careful dosing may minimize the tendency of bupropion to cause seizures. The daily dosage should not exceed 450 mg, and no single dose should exceed 150 mg. Sudden dosage increases should also be avoided. The dosage should not be increased by more than 100 mg a day over a three-day period. An appropriate initial dosage is 200 mg per day, increasing to 300 mg per day on the fourth day. While some investigators have noted improvement as early as one week after initiation of therapy, maximal therapeutic action is usually not evident until the fourth week of therapy. The dosage should not be increased until this trial period has elapsed. Bupropion should be discontinued in patients who do not respond to 450 mg per day after an appropriate period of observation. [2]

To reduce the risk of side effects, bupropion should be maintained at the lowest effective dosage. The long-term effects of bupropion are not well established. Therefore, the drug should be discontinued after several months of therapy.

Fortunately, all patients who have taken an overdose of bupropion (up to 4,200 mg) have recovered without serious complication. [2,19] No specific antidote is available; the usual supportive therapy provided in cases of poisoning is sufficient.

REFERENCES

[1] Kline NS. Antidepressant medications. A more effective use by general practitioners, family physicians, internists, and others. JAMA 1974; 227:1158-60.

[2] Drug facts and comparisons. Philadelphia: Facts and Comparisons Div., Lippincott, 1990: 1124-8.

[3] Bupropion for depression. Med Lett Drugs Ther 1989; 31:97-8.

[4] Ferris RM, Cooper BR, Maxwell RA. Studies of bupropion's mechanism of antidepressant activity. J Clin Psychiatry 1983; 44 (5 Pt 2): 74-8.

[5] Bryant SG, Brown CS. Current concepts in clinical therapeutics: major affective disorders. Part I. Clin Pharm 1986; 5:304-18.

[6] Sulser F. Mode of action of antidepressant drugs. J Clin Psychiatry 1983; 44(5 Pt 2):14-20.

[7] Rudorfer MV, Potter WZ. Antidepressants. A comparative review of the clinical pharmacology and therapeutic use of the 'newer' versus the 'older' drugs. Drugs 1989; 37:713-38.

[8] Golden RN, James SP, Sherer MA, Rudorfer MV, Sack DA, Potter WZ. Psychoses associated with bupropion treatment. Am J Psychiatry 1985; 142:1459-62.

[9] Golden RN. Diethylpropion, bupropion, and psychoses [Letter]. Br J Psychiatry 1988; 153: 265-6.

[10] Lai AA, Schroeder DH. Clinical pharmacokinetics of bupropion: a review. J Clin Psychiatry 1983; 44(5 Pt 2):82-4.

[11] Pitts WM, Fann WE, Halaris AE, et al. Bupropion in depression: a tri-center placebo-controlled study. J Clin Psychiatry 1983; 44(5 Pt 2):95-100.

[12] Freighner JP, Meredith CH, Stern WC, Hendrickson G, Miller LL. A double-blind study of bupropion and placebo in depression. Am J Psychiatry 1984; 141:525-9.

[13] Zung WW. Review of placebo-controlled trials with bupropion. J Clin Psychiatry 1983; 44(5 Pt 2):104-14.

[14] Othmer SC, Othmer E, Preskon SH, Mac D. Differential effect of amitriptyline and bupropion on primary and secondary depression: a pilot study. J CLin Psychiatry 1988; 49:310-2.

[15] Halaris AE, Stern WC, Van Wyck Fleet J, Reno RM. Evaluation of the safety and efficacy of bupropion in depression. J Clin Psychiatry 1983; 44(5 Pt 2):101-3.

[16] Feighner J, Hendrickson G, Miller L, Stern W. Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder. J Clin Psychopharmacol 1986; 6:27-32.

[17] Othmer E, Othmer SC, Stern WC, Van Wyck Fleet J. Long-term efficacy and safety of bupropion. J Clin Psychiatry 1983; 44(5 Pt 2):153-6.

[18] Farid FF, Wenger TL, Tsai SY, Singh BN, Stern WC. Use of bupropion in patients who exhibit orthostatic hypotension on tricyclic antidepressants. J Clin Psychiatry 1983; 44(5 Pt 2):170-3.

[19] Wenger TL, Stern WC. The cardiovascular profile of bupropion. J Clin Psychiatry 1983; 44(5 Pt 2):176-82.

[20] Peck AW, Stern WC, Watkinson C. Incidence of seizures during treatment with tricyclic antidepressant drugs and bupropion. J Clin Psychiatry 1983; 44(5 Pt 2):197-201.

[21] Davidson J. Seizures and bupropion: a review. J Clin Psychiatry 1989; 50:256-61.

[22] Dessain EC, Schatzberg AF, Woods BT, Cole JO. Maprotiline treatment in depression. A perspective on seizures. Arch Gen Psychiatry 1986; 43:86-90.

MICHAEL FEINBERG, M.D., PH.D., Professor of Mental Health Sciences Hahnemann University School of Medicine, Philadelphia, Pennsylvania

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