Consensus statements on the clinical understanding and use of bupropion in Hong Kong

Abstract Objectives To develop a local consensus to guide medical practitioners and psychiatrists on the use of bupropion in different psychiatric conditions in Hong Kong. Methods By utilizing the modified Delphi technique, a group of 10 local physicians with extensive experience in the management of major depressive disorder (MDD) developed and voted (using an anonymous, electronic voting system) on the practicality of recommendation of a set of consensus statements on the clinical use and understanding of bupropion in Hong Kong. Results There was a very high degree of agreement among the panelists on the 11 finalized consensus statements. Conclusions The present consensus statements are developed as general recommendations for medical practitioners and psychiatrists to be practically referred to in clinical settings.

The consensus group utilized the modified Delphi technique to allow formal face-to-face expert focus meeting. 4 After a comprehensive review and discussion, eleven statements on bupropion were finalized and voted anonymously using electronic voting devices.
Each statement was rated according to both (a) quality of evidence and (b) practicability of recommendation in Hong Kong. A consensus statement was only accepted if ≥80% voted "A" or "B" for practicability (Table 1).

| RE SULTS
Statement 1: Besides treatment for major depressive disorder, bupropion is also indicated for seasonal affective disorder and is particularly useful for patients with anhedonia, reduced motivation, weight concern, and sexual dysfunction.
Quality of evidence: I Practicability of recommendation: A-100%, B-0%, C-0%, D-0%, E-0% In Hong Kong, bupropion is indicated for the treatment of MDD and seasonal affective disorder. 5 The efficacy and safety profile of bupropion have been demonstrated in several studies. 1,2,[6][7][8] Bupropion resulted in similar effectiveness as compared to sertraline, although the side effects were significantly more common in sertraline-treated patients. 6 In particular, orgasm or sexual dysfunction was less common in bupropion-treated patients. 1,8 Sexual dysfunction was reported as an adverse event by <1% of the patients, 1 suggesting that bupropion may be the antidepressant of choice in regard to the avoidance of sexual dysfunction.
Bupropion provides greater relief to anhedonia, fatigue, and low energy, which are the most common symptoms associated with MDD patients, occurring in at least 70% of the patients. 9,10 As bupropion is also associated with weight loss, 1,2 it will also be particularly useful for patients with weight concerns. The use of bupropion as an aid in smoking cessation was supported by high-quality evidence. 3,11,12 It has been shown that bupropion is effective and well tolerated in adult smokers, both healthy and medically ill with cardiovascular disease or chronic obstructive pulmonary disease (COPD). 3 In a longer study, bupropion has also been shown to be able to delay relapse to smoking across 1 year. 3 Patients suffering from bipolar depression can benefit from bupropion, with a low rate of manic switch, and bupropion can also be useful to relieve adult ADHD symptoms. 3 Accumulating evidence has also shown that bupropion is efficacious in reducing depression-related anxiety symptoms. However, the effect has not been extensively investigated. 3 Patients with depression in Parkinson's disease could also benefit from the use of bupropion, although no randomized controlled

Practicability of recommendation
I: Evidence obtained from at least 1 randomized controlled trial.
A: There is good evidence to support the statement.
A: Accept completely.
II-1: Evidence obtained from well-designed control trials without randomization.
B: There is fair evidence to support the statement.
B: Accept with some reservation.
II-2: Evidence obtained from welldesigned cohort or case-control study.
C: There is poor evidence to support the statement, but recommendation made on other ground(s).
C: Accept with major reservation. trial has been conducted. [13][14][15] Because depression in Parkinson's disease has been linked to cerebral dopaminergic hypoactivity, commonly prescribed antidepressant treatments such as tricyclic antidepressants (TCA), selective serotonin reuptake inhibitor (SSRI), and serotonin-norepinephrine reuptake inhibitor (SNRI), which lack dopaminergic activity, may not be effective. 13 Bupropion, with its intrinsic dopaminergic action, may be a better choice in this aspect.

Statement 3: Bupropion is a unicyclic antidepressant with
dual action on dopamine and noradrenaline, but has no effect on serotonin.
Quality of evidence: II-2 Practicability of recommendation: A-100%, B-0%, C-0%, D-0%, E-0% Bupropion is classified as an atypical antidepressant, where it specifically acts as a dual norepinephrine and dopamine reuptake inhibitor (NDRI) at clinically relevant doses. [16][17][18] The inhibition of serotonin uptake by bupropion and its metabolites has been shown to be negligible even at the highest concentration tested. 16 The safety profile of bupropion has been studied extensively in thousands of clinical trial subjects and in over 40 million patients who have received bupropion clinically. 3,5 Bupropion has been shown to be generally well tolerated and resulted in a relativity low rate of discontinuation. 3 Insomnia is usually transient and can be avoided by not taking bupropion near or at bedtime. In addition, the consensus group acknowledged that dry mouth is relatively common in Chinese patients. Cautions should be exercised when prescribing bupropion in patients with hypertension or cardiovascular comorbidities. Although the use of bupropion as a monotherapy has not been associated with effects on blood pressure as compared to placebo in clinical trials, the risk in elevated blood pressure is increased if bupropion is used in a combination therapy with other drugs that also affect the dopaminergic and noradrenergic activity. 3 Bupropion should not be used in patients with closed-angle glaucoma due to the risk of angle-closure attack. 5 Bupropion is also not recommended in patients that have or had an eating disorder such as bulimia. 5 Similar with SSRI, bupropion is also associated with the risk of seizure, where the rate increases substantially at doses above 450 mg/d. 3 The group acknowledged the suggestion to exclude patients with past history of epilepsy and to screen patients for comorbidities or medications that may lower seizure threshold. There is no evidence for kinetic interactions between smoking or alcohol with bupropion. 12,22 Zinc supplement might produce synergistic effects when given in combination with bupropion 23 ; physicians should be aware of this interaction. There are contradicting study results regarding the effect of bupropion on the risk to fetal cardiac malformation during the first trimester of pregnancy. [30][31][32][33][34] Nevertheless, the consensus group agreed that there is an elevated risk for it. A statistically significant association between bupropion and fetal cardiac malformation was found, although the magnitude of the observed risks was small. 30,33 Ideally, the obstetrician and psychiatrist should work together to assess the risk/benefit of using bupropion and counsel the patient on the potential risk for the developing fetus. 30

| CON CLUS ION
The consensus group has unanimously reached an agreement on 11 statements regarding the use of bupropion in Hong Kong. The present consensus statements are developed as general recommendations for medical practitioners and psychiatrists to be practically referred to in clinical settings.

ACK N OWLED G M ENTS
The authors would like to acknowledge the Asian Association of Neuropsychopharmacology (AANP) for supporting the consensus meeting. Medical writing assistance was provided by Best Solution Co. Ltd. and funded by the AANP. This study did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The decision to submit the article for publication was made by all members of the consensus group without any commercial influence.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

M I SS I O N O F TH E A A N P
The AANP aims to become the recognized forum to foster ongoing local and international collaboration, on education intended to advance the treatment of all aspects of mood disorder and psychotic illnesses, particularly schizophrenia, and to improve the outcomes and quality of life for those who suffer from psychiatric illness and for their carers and family members.