Let’s Learn Psychopharmacology A to Z: Bupropion

“Happiness is not something you have to achieve. You can still be happy during the process of achieving something. So if you change your perspective a bit, although many of you may be going through tough times right now, this could also be the most beautiful moment of our lives.”


Kim Nam-joon, 2015. “The Most Beautiful Moment In Life Concert” Seoul, South Korea

Welcome to another post in the “Let’s Learn Psychopharmacology A to Z” series! This series is dedicated to discussing some of the most highly-cited, landmark articles in psychopharmacology.

Disclaimer: This discussion is intended to briefly and superficially review the medical literature that describes the use of a medication. As new studies are published every day, information presented here may be obsolete. Ultimately, selecting a medication remains a decision between a patient and their doctor. Doctors recommending and patients using these medications are strongly advised to consult information provided by the manufacturer.

Today’s topic is bupropion (brand names: Wellbutrin, Aplenzin, Zyban [branded for smoking cessation]).

First, let’s have some background. Bupropion is a norepinephrine and dopamine reuptake inhibitor. Since dopamine is inactivated by norepinephrine reuptake in the frontal cortex, which largely lacks dopamine transporters, bupropion can increase dopamine neurotransmission in this part of the brain (Stahl 2017). Bupropion is FDA-approved for major depressive disorder, seasonal affective disorder, and nicotine addiction. It is also used off-label for bipolar depression, ADHD, and sexual dysfunction. Bupropion decreases depression relapse and also extends time to relapse for depression (Weihs et al 2002). Studies comparing bupropion and SSRIs have all shown comparable efficacy (Clayton 2007).

Bupropion is offered in three formulations: immediate release (IR), sustained release (SR), and extended release (XL). Both SR and XL formulations are FDA approved for major depressive disorder. Only the SR formulation is FDA approved for nicotine addiction. Bupropion can be used with SSRIs (such as citalopram or sertraline) to treat partial responders or to improve SSRI-induced apathy and SSRI-induced sexual dysfunction. Bupropion is also used as an augmenting agent to mood stabilizers and/or atypical antipsychotics (such as lithium or olanzapine) in bipolar depression. 

This brings me to today’s discussion, which I am titling, “Bupropion Mythbusters.” As I reviewed literature for this post, I was surprised that a number of oft-repeated “truths” by my colleagues and mentors were, in fact, not so firmly set in stone. Some may be controversial, or perhaps the data simply isn’t conclusive. In any case, I have selected three which impressed me the most and presented them below.

!!! Bupropion Mythbusters !!!

Myth #1: More is Better

Guidelines allow for use of up to a total of bupropion 450 mg daily for the treatment of depression, with most patients taking a 300 mg daily dose. But there is little to no evidence of a clear dose-response effect. One 8-week multicenter study of bupropion SR showed no difference between 150 and 300 mg daily doses measured on depression rating scales (Reimherr et al 1998). A possible explanation for this is presented in an early study that demonstrated a potential inverted curvilinear plasma concentration-response curve for bupropion, meaning that concentrations above or below the maximum response range may correlate with a poor response for depression (Preskorn 1983). 

This finding may not be absolute. In contrast, there is a positive linear dose- and concentration-response observed for smoking cessation with bupropion. Johnston et al showed that higher daily doses of bupropion were correlated with increased likelihood of smoking cessation, up to 300 mg daily. 

In practice, I would still support increasing doses of bupropion for depression, as it may help some patients reach the maximum response range. However, my expectations for symptom reduction would be guarded. 

Myth #2: Bupropion will make anxiety worse

Hypothetically, bupropion may increase anxiety due to its stimulant properties. However, this theory has remained unproven. A randomized, parallel-group, double blind, multicenter trial compared anxiety response between sertraline (n=126) and bupropion SR (n=122) in people with major depressive disorder. No difference in anxiolytic efficacy or time-to-treat effect was observed between the two groups. Furthermore, there was no evidence for worsening of anxiety with bupropion over the course of the 16-week trial (Rush et al 2001). In a review article, Foley et al state that in their experience, anxiety is an occasional self-reported cause of intolerance, yet bupropion also appears to lower anxiety in the majority of psychiatric patients. These findings suggest that bupropion is not anxiogenic.

Myth #3: Stop bupropion for smoking cessation if there isn’t an intent to quit smoking

Bupropion is useful in improving both initial and long-term abstinence rates and at preventing relapse (Ferry 2003). Its principal mode of action seems to be the alleviation of withdrawal symptoms following smoking cessation. A randomized, double-blind trial comparing bupropion versus placebo showed that bupropion may be used long-term in people who are unwilling to quit or who perceive themselves as being unable to quit smoking. Fourteen percent in the bupropion group sustained a 4-week continuous abstinence period versus 8% in the placebo group. The researchers also showed that the number of cigarettes smoked per day and the time until the next cessation attempt were decreased during bupropion treatment (Hatsukami 2004). Therefore, bupropion can provide a positive benefit even in the absence of intent to stop or cut down tobacco use. The effects are not sustained after bupropion is discontinued. 

In conclusion, bupropion has been widely studied for a variety of uses and has been proven to be safe and effective. Its unique mechanism of action relative to other SSRIs and SNRIs make it a valuable option in antidepressant treatment.

References

Stahl, Stephen M, and Meghan M. Grady. Stahl’s Essential Psychopharmacology: Prescriber’s Guide. 2017. Print.

Weihs KL, Houser TL, Batey SR et al. Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression. Biol. Psychiatry 51(9), 753–761 (2002).

Clayton AH . Extended-release bupropion: an antidepressant with a broad spectrum of therapeutic activity? Expert Opin Pharmacother 2007 ; 8 (4): 457 –66. 

Reimherr FW, Cunningham LA, Batey SR et al. A multicenter evaluation of the efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets versus placebo in depressed outpatients Clin. Ther. 20(3), 505–516 (1998). 

Preskorn SH. Antidepressant response and plasma concentrations of bupropion. J. Clin. Psychiatry 44(5 Pt 2), 137–139 (1983).

Johnston JA, Fiedler-Kelly J, Glover ED et al. Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob. Res. 3(2), 131–140 (2001).

Rush AJ, Trivedi MH, Carmody TJ et al. Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline. Neuropsychopharmacology 25(1), 131–138 (2001).

Foley KF , DeSanty KP , Kast RE . Bupropion: pharmacology and therapeutic applications . Expert Rev Neurother 2006 ; 6 (9): 1249 –65. 

Ferry L , Johnston JA . Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience . Int J Clin Pract 2003 ; 57 (3): 224 –30. 

Hatsukami DK, Rennard S, Patel MK et al. Effects of sustained-release bupropion among persons interested in reducing but not quitting smoking. Am. J. Med. 116(3), 151–157 (2004).

Let’s Learn Psychopharmacology A to Z: Acamprosate

“Better is possible. It does not take genius. It takes diligence. It takes moral clarity. It takes ingenuity. And above all, it takes a willingness to try.”


Better: A Surgeon’s Notes on Performance, Atul Gawande

Welcome to the first post to start the “Let’s Learn Psychopharmacology A to Z” series! Through this series, I will discuss some of the most highly-cited, landmark articles in psychopharmacology. A lot of this knowledge is relatively new. Medications were introduced into the practice of psychiatry in the 1950’s starting with the use of chlorpromazine and lithium. Since then, the list of psychotropic medication has exploded. There are 143 drugs described in Stahl’s Essential Psychopharmacology, Prescriber’s Guide, Sixth Edition (which is a highly recommended reference material decorating many psychiatrists’ offices) and more are being developed in pharmaceutical pipelines.

Disclaimer: This discussion is intended to briefly and superficially review the medical literature that describes the use of a medication. As new studies are published every day, information presented here may be obsolete. Ultimately, selecting a medication remains a decision between a patient and their doctor. Doctors recommending and patients using these medications are strongly advised to consult information provided by the manufacturer.

Today’s topic is acamprosate (brand name: Campral).

Let’s start with basic facts. Acamprosate is an amino acid derivative of taurine that acts as a modulator of GABA neurotransmission. It is FDA-approved for maintenance of alcohol abstinence. Theoretically, it reduces excitatory glutamate neurotransmission and increases inhibitory GABA neurotransmission. Because alcohol withdrawal can lead to excessive glutamate activity and deficient GABA activity, acamprosate can act as “artificial alcohol” to mitigate these effects.

"How Acamprosate Works" © Jennifer Hsu
“How Acamprosate Works” © Jennifer Hsu

Acamprosate appears to work best for individuals who have already abstained from alcohol. Other medications used frequently for alcohol use disorder include naltrexone and disulfiram.

In 2004, Bouza and colleagues published a meta-analysis of 13 acamprosate studies with 4000 total participants. The major findings confirmed that acamprosate improved the continuous abstinence rate with a number needed to treat of 10, and also significantly improved cumulative abstinence. Unfortunately, this study also showed that the rate of adherence to prescribed medication was a problem. Compliance varied widely among the studies, ranging between 40% to 90%. Overall, only about half of the people receiving acamprosate continued to take it throughout the assigned treatment period. The reasons for drop-out are unclear, though a minority reported discontinuation of medication due to adverse side effects, with gastrointestinal issues affecting approximately 17% of patients assigned to take acamprosate.

Next up is a randomized controlled trial – the COMBINE study, which was published in JAMA in 2006.

The COMBINE study is one of the largest studies on acamprosate. It was a randomized controlled trial that studied medication management (MM) and combined behavioral intervention (CBI) for the treatment of alcohol use disorder. Medications used include acamprosate and naltrexone. Primary outcome measures were 1) percent days abstinent and 2) time to first heavy drinking day. A heavy drinking day was defined as ≥ 4 drinks per day for women and ≥ 5 drinks per day for men

Participants were first divided into three groups: 1) MM only, 2) MM+CBI, and 3) CBI only. Within the groups that received medication management (MM), participants were further divided into four groups: acamprosate only, naltrexone only, both acamprosate + naltrexone, and placebo. This resulted in nine total groups.

Surprisingly, the COMBINE study showed that acamprosate had no significant effect on drinking versus placebo, either by itself or with any combination of naltrexone, CBI, or both. This result was different from the prior studies. The authors hypothesize that the negative result is perhaps because the COMBINE trial required only 4 days of abstinence before participants could join the trial, versus a longer pretreatment abstinence period.

A meta-analysis published in 2008 stated that acamprosate is efficacious, but in different ways than naltrexone. Rösner and colleagues write that acamprosate improves continuous abstinence rates over placebo with a number needed to treat of 8. However, acamprosate did not influence alcohol consumption after the first drink (i.e. reducing the amount consumed or risk of a lapse becoming a relapse.) Naltrexone reduced relapse rates, time to relapse, and also reduced heavy drinking in a subgroup of non-abstinent patients. From this, acamprosate appears to be the treatment of choice if the goal is complete abstinence, whereas naltrexone is preferred if choosing a harm-reduction strategy to prevent excessive drinking in non-abstinent patients.

“Individually allocating patients to treatments according to their motivational status could further enhance the effectiveness of treatments of alcohol dependence.”


– Rösner and colleagues 2008, citation below

The final article presented here was published in 2008 by Kranzler and colleagues. This report contributed to the United States Food and Drug Administration (FDA) approval of acamprosate for use in conjunction with psychosocial support in the maintenance of abstinence in alcohol-dependent patients. Kranzler et al re-analyzed three European pivotal trials, which were published in 1995, 1996, and 1997. These trials took place in France, Belgium, and Germany and examined a total of 623 patients.

Krazler et al applied a more rigorous definition of abstinence than the initial studies; for example, patients with missing data or with unknown status were also considered non-abstinent. With a more restrictive definition of abstinence, the calculated rates of abstinence were lower than the rates previously published, but remained significantly higher for patients treated with acamprosate than placebo. Rates of complete abstinence for placebo ranged between 9-13%, while rates for acamprosate ranged from 16-38%. Secondary outcomes for percent days abstinent and time to first drink also showed efficacy favoring acamprosate.

Overall, acamprosate is a well-studied, safe, and effective medication. There is also some evidence to show that the benefits of acamprosate in maintaining sobriety can extend for at least up to 12 months after drug discontinuation. Acamprosate has some limitations in its use. For example, it is most likely to be successful in people who have already maintained a period of sobriety. However, it can still be a valuable treatment option for many people.

References

Bouza C, Angeles M, Muñoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction. 2004 Jul;99(7):811-28. doi: 10.1111/j.1360-0443.2004.00763.x. Erratum in: Addiction. 2005 Apr;100(4):573. Magro, Angeles [corrected to Angeles, Magro]. PMID: 15200577.

Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3;295(17):2003-17. doi: 10.1001/jama.295.17.2003. PMID: 16670409.

Rösner S, Leucht S, Lehert P, Soyka M. Acamprosate supports abstinence, naltrexone prevents excessive drinking: evidence from a meta-analysis with unreported outcomes. J Psychopharmacol. 2008 Jan;22(1):11-23. doi: 10.1177/0269881107078308. PMID: 18187529.

Kranzler HR, Gage A. Acamprosate efficacy in alcohol-dependent patients: summary of results from three pivotal trials. Am J Addict. 2008 Jan-Feb;17(1):70-6. doi: 10.1080/10550490701756120. PMID: 18214726.