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.

A Brief Discussion on the International Pilot Study of Schizophrenia

I’ve been trying to make a renewed and dedicated effort to both read and write more. I’ve realized that waiting for the inspiration to strike doesn’t happen. If I want to read and write more, then I need to set aside time to cultivate the skill. It has been more difficult that I thought.

Still, this is part of that effort. And so today, I decided to review and write about my thoughts on a very important psychiatric article – The International Pilot Study of Schizophrenia: five-year follow-up findings.

Published in 1992, this article is an “oldie but goodie.” It is best known for its provocative finding that people with schizophrenia have better clinical and social outcomes in developing countries when compared with developed countries. In other words, a person with schizophrenia in Agra (India) or Ibadan (Nigeria) was significantly less ill and suffered less occupational and social impairment than someone with the same diagnosis in London (United Kingdom) or Washington, DC (United States).

As discussed in the article, one suggested explanation for this finding is incompleteness of follow-up at the sites in developing countries. However, when they further examined the data, they found that this was an unsatisfactory explanation for the results. A second suggested explanation was if a greater proportion of patients in developing countries had an acute, rapidly resolving psychosis with an inherently better prognosis. This explanation, too, was not supported upon further data modeling.

A third proposed explanation involved greater tolerance and acceptance of the behaviors displayed by people with schizophrenia by their families. This hypothesis had partial support, as a sub-study related to this project showed that patients in Chandigarh (India) who had families with low levels of Expressed Emotion had better clinical outcomes.

Low levels of Expressed Emotions are favorable; alternatively, families with high Expressed Emotion interact more frequently with negative and intense verbal exchanges. Relationships are oppositional or conflictual in nature, and interaction patterns are rigid. Conversations are marked by increased criticism, hostility, and emotional overinvolvement. As described by Amaresha & Venkatasubramanian in a 2012 article, “Researchers have positioned Expressed Emotion within the diathesis-stress model of psychopathology, characterizing it as an environmental stressor that can potentially precipitate/cause relapse of psychosis among people with a genetic vulnerability.”

However, the study concluded with a statement that an exact definition of the elements of culture and society that improve outcomes remains unclear.

There have been additional follow-up studies to this impactful article. In 2000, Hopper and Wanderling revisited this question and hypothesized that cultural factors promoting recovery may include: 1) supportive kin, 2) auspicious or alternative beliefs, 3) flexibly configured work, 4) forgiving domestic space, and 5) more socially integrated subjectivities. They also point out that, subtracting Hong Kong, the remaining sites in the “developing” group are all located within India, which simplifies the question of culture.

“The extraordinary engagement of Indian families in the course of treatment – from the initial decision to seek help, to attending to basic needs and medication adherence during hospitalization, to support afterward, including monitoring medications and functioning – is surely one of the signature features of psychiatry in that country.”


Hopper & Wanderling 2000, “Revisiting the Developed Versus Developing Country Distinction in Course and Outcome in Schizophrenia.”

I can further appreciate this finding while I was reading The Quiet Room by Lori Schiller. The Quiet Room is a biography describing one woman’s experience with schizophrenia. About midway into the book, Lori’s mother realizes that she had seen her own mother, Lori’s grandmother, display the eccentric and psychotic behaviors that Lori appeared to be experiencing. Lori underwent multiple psychiatric hospitalizations and trials of medications. Meanwhile, Lori’s grandmother, who was the daughter of a wealthy man and a housewife, did not. As a quote from the book describes, “My mother [Lori’s grandmother] was rich, and so she was allowed to be eccentric.” (Schiller & Bennett 1994, pg 82)

Lori, who faced the pressures of being a high-achieving, upper-middle class young adult, newly graduated from college, suffered greatly not just from the symptoms of psychosis but also from the loss of her place in society.

“I have lost many things: the career I might have pursued, the husband I might have married, the children I might have had.  During the years when my friends were marrying, having their babies and moving into the houses I once dreamed of living in, I have been behind locked doors.”


Schiller & Bennet 1994, The Quiet Room, pg 5

It brings to mind the pressures that society may place on its members to conform. Of course, conforming is not necessarily bad. Conforming to social norms regulates our social interactions, reduces anxiety, brings us closer to one another, and helps us feel safe. But perhaps there is a price for conformity – a price that is paid by the marginalized among us.

References

Leff J, Sartorius N, Jablensky A, Korten A, Ernberg G. The International Pilot Study of Schizophrenia: five-year follow-up findings. Psychol Med. 1992 Feb;22(1):131-45.

Hopper K, Wanderling J. Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. Schizophr Bull. 2000;26(4):835-46.

Amaresha AC, Venkatasubramanian G. Expressed emotion in schizophrenia: an overview. Indian J Psychol Med. 2012;34(1):12-20.

Schiller, L., & Bennett, A. The Quiet Room: A Journey Out of the Torment of Madness. New York: Warner Books. 1994.