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.

Hiroshima

In April, I went to Japan for three weeks for vacation. I chose a handful of cities to visit and spent few days in each. One of these was Hiroshima, where I visited the Peace Memorial dedicated to the people who were killed in the atomic bombing on August 6, 1945.

Before I went to the memorial, I don’t think that I understood the devastation of nuclear weapons. I knew that the bombs released enormous amounts of heat and radiation, and that the aftereffects of radiation exposure such as cancer were horrible. Knowing wasn’t the same as seeing photographs of the sick and dying, or the ragged, blood-stained uniforms the schoolchildren had worn, or hearing the stories narrated by survivors, most of whom had been children and are now old men and women.

The exhibit is constantly changing, especially as society changes and living memory fades. At the time, the main museum was undergoing renovation, but there were others nearby, including a special exhibit titled “The Twinkling Stars Know Everything,” after a collection of stories by the mothers and fathers of first-year students of Hiroshima Itchu Junior High School. The school was located only a kilometer away from the hypocenter of the bomb, and nearly the entire class died. They were only thirteen years old.

I learned about another collection of stories at the memorial and decided to read it: Hiroshima, by John Hersey. Originally published in The New Yorker, this book follows the lives of six people who were present in the bombing.

Genbaku “A-bomb” Dome © Jennifer Hsu

Of the six, the individual who most caught my interest was Dr. Terufumi Sasaki, a 25-year-old surgeon who had just completed his training at the Eastern Medical University in China. I felt great empathy with this young physician, as I am similar in age and stage of training. Dr. Sasaki was working in the Red Cross Hospital in Hiroshima. When the bomb fell, he found himself to be one of the few uninjured physicians on staff, and soon he and the other physicians were overwhelmed by the thousands of injured who came to the hospital for help.

Quote from the book:

“By three o’clock the next morning, after nineteen straight hours of his gruesome work, Dr. Sasaki was incapable of dressing another wound. He and some other survivors of the hospital staff got straw mats and went outdoors — thousands of patients and hundreds of dead were in the yard and on the driveway — and hurried around behind the hospital and lay down in hiding to snatch some sleep. But within an hour wounded people had found them; a complaining circle formed around them: “Doctors! Help us! How can you sleep?” Dr. Sasaki got up again and went back to work. Early in the day, he thought for the first time of his mother, at their country home in Mukaihara, thirty miles from town. He usually went home every night. He was afraid she would think he was dead.” – Hersey, J. Page 25

I can hardly imagine how exhausted and terrified he must have been.

Hiroshima is one of the most striking and terrifying proofs of the horrors of war. But my visit there also showed me the greatness of the human spirit and the possibility of forgiveness and healing. At the memorial, I stopped to listen to a student choir – one of many which take place throughout the year, dedicated to the children killed in the bombing – when a Japanese man turned to me and attempted to give me a pamphlet. When I indicated that I could not read Japanese, he used broken English to tell me about why the students were singing. Then he asked where I came from. When I said that I came from America, he smiled broadly and said that he loved Americans, and that he hoped to travel across the world to visit our country one day, too.

More Information

Hersey, J. Hiroshima. Vintage Books, NY. Reprint edition, 1989.

Ikegami, N. The Twinkling Stars Know Everything. First English Edition edition, 1984.

I Am Not Sick, I Don’t Need Help

Have you ever been in denial?

Recently I have been pinching myself in disbelief. Am I really graduated from medical school? Are people actually going to start calling me “doctor?” Wow! It is terrifying, yet exciting. As a fresh graduate, I know that I still have a long road ahead of me before becoming a board-certified physician, but right now I have been feeling so incredibly blessed.

This period of time between graduation and the beginning of residency has been incredibly relaxing. I spent most of it vacationing. In April, I traveled throughout Japan for three blissful weeks. Then, I went on a scenic car trip from Texas and all the way up through New Mexico, Nevada, and Idaho to Washington State. Beautiful, isn’t it?

Driving by the Sierra Nevada © Jennifer Hsu

During these trips, I also read several books. One of these is “I Am Not Sick, I Don’t Need Help” by Xavier Amador, Ph.D., a clinical psychologist. I found it to be a quick, pleasurable read, because of the author’s concise and clear writing style. He also does a spectacular job of evoking empathy and understanding through clinical vignettes and personal stories.

If you know somebody with serious mental illness who is in “denial” and refuses to seek treatment or take medication, then this book is for you.

Dr. Amador divides this book into five parts. The first part provides information about mental illness, particularly schizophrenia. The second part describes the LEAP (listen, empathize, agree, partner) methodology that Dr. Amador developed, which has shown positive results in his work with patients and their families. The third part focuses on the feelings of betrayal and guilt that a patient and their family may feel when the patient is taken against their will to the hospital, and how to re-build trust. The fourth part discusses the value of assessing a person’s awareness of their illness and its purpose in formulating a cooperative treatment plan.

The fifth section is the most memorable of all. In it, Dr. Amador tells us about his brother Henry, who was diagnosed with schizophrenia. I could feel the love and care between the brothers, nearly palpable from the page, and I admired that he shared his brother’s story with us. It is a poignant reminder that every patient, no matter how “crazy” or psychotic, is loved by somebody. I admit that I shed some tears reading Henry’s story.

I highly recommend this book for anyone with a family member with mental illness. It is also a wonderful read for any health professionals.

Key Takeaways
  • “Denial” is the wrong term for poor insight in a person with mental illness. In patients with schizophrenia, the executive (frontal) part of the brain is often dysfunctional, resulting in a symptom called anosognosia, which is the condition in which a person with a disability seems unaware of its existence.
  • Reflective listening is listening with only one goal: to understand. It is not commenting, disagreeing, judging, or reacting in any way.
  • It is not necessary for the patient to believe that they have a mental illness. But, it is necessary for the patient and their support network (family, health provider) to work together for success. Prioritize finding common ground and collaboration, not arguing over who is “right.”
Quotes

“I can’t guarantee that LEAP will definitely eliminate medication and service refusal in the person you’re trying to help, but I can promise that if you faithfully follow the guidelines I give, they will help lower tension, increase trust, and greatly increase the likelihood that the person you are trying to help will follow your advice.” – Amador, X. Page 3.

“I have never talked anyone out of a delusion and, to my knowledge, I have never talked anyone into one either. The point is, when you’re facing someone who rigidly holds irrational beliefs, you gain nothing by disagreeing.” – Amador, X. Page 84.

“I loved Henry, and when someone you love is in pain, it is hard not to empathize. Learning to listen lead to empathy. And my empathy ultimately resulted in my brother showing a real interest in my thoughts about the illness he felt he did not have and the medications he was sure he did not need.” – Amador, X. Page 113.

More Information

Amador, X. I Am Not Sick I Don’t Need Help! How to Help Someone with Mental Illness Accept Treatment. Vida Press. Kindle Edition. 2012.

“LEAP®”; “L.E.A.P.®“;“Listen-Empathize-Agree-Partner®”; “Listen, Empathize, Agree, Partner®” and all similarly punctuated versions are registered trademarks of the LEAP Institute, are protected under the laws of the United States Patent and Trademark Office (USPTO), and may not be used without express license of the LEAP Institute.

Learn more at https://leapinstitute.org

A Day with Monet

A few days ago, I went to see an exhibition of the early years of Claude Monet, a French artist, at the Kimbell Art Museum.

A classmate of mine had managed to procure free tickets for a small group tour and invited me along. I was assigned to be on call that day, but could not pass up the opportunity. After explaining to my residents and attending, they graciously allowed me to leave the hospital an hour early to attend.

I saw over fifty paintings, from his first studies of landscaping to his eventual move towards Impressionism. It was an awe-inspiring journey of color and expression and story of a young, struggling artist.

magpie-monet
The Magpie
Claude Monet, 1869

At the museum, I also learned a new word. A docent is “a person who leads guided tours especially through a museum or art gallery.” How posh, I thought. The word seemed to convey education and expertise. And indeed, the docent who guided our group had a vast pool of knowledge about the paintings displayed. She knew from which museum or collection each painting had been procured. She knew where Monet had painted each piece. She explained how two seemingly very different paintings could simply be two different points of views. How many times had she given this same presentation? Yet as I watched her speak, I could see her delight and joy in the simple act of sharing her passion for art.

do·cent | noun | ˈdōsənt | a person who leads guided tours especially through a museum or art gallery

The docent told us that Monet and other Impressionists rebelled against the tradition of painting shadows in grey or black. They saw that there were colors to be discovered in shadows too. Critics initially rejected Monet’s famous snowscape The Magpie (see above) for its innovative depiction of shadow using delicate tones of blue. Today it is hailed as one of his best work.

As I listened, I thought about the importance of balancing tradition with transformation. Monet had been trained as a traditional landscape artist before beginning to branch out into new studies of light and shadow. Without that foundation of study, perhaps he would not have been as successful. Yet he also did not allow himself to be entrenched in the “rules” of his work. Likewise, my medical school has given me a foundation to build upon. But my learning will surely never end. In the course of my career, I will see vast changes and discoveries. What colors lay hidden in the shadows of medicine? Will I be able to learn and adapt?

Afterwards, my friends and I went out for dinner. It was wonderful to see them again. Last year, I saw my classmates nearly every day. Now as third years, we are all busy running around in our different electives and choosing our future path.

Of course, as with any collection of medical students, we had the usual circle where we all went around and talked about how our minds have changed after more exposure to different specialties. A former aspiring radiologist now has her mind set on obstetrics. A former hopeful surgeon now wants to do pain management. Last year, I thought of becoming a neurologist or internist – now I have decided on psychiatry.

My declaration was not met with surprise.

“I wouldn’t have guessed it, but I can see it,” one person told me. “It suits you.”

“He’s calling you insane,” someone else joked.

Then we talked about the exhibit.

“When I’m a resident, I’d like to involve art in my study,” someone said. “After all, medicine is both a science and a humanity.”

I thought of the dozens of patients whom I have met over the last six months. I thought of all the challenges that we had yet to face and all the lessons we will learn. I thought of the docent and her love of art. I thought of Monet and the Impressionists and their shadows of color and light.

I couldn’t agree more with my friend.

The Right Things

Everything must be used until it falls apart. Clothing should be worn and handed down until it became threadbare. No grain of rice should be wasted.

The man walks up to the volunteer table where we are performing free blood pressure and glucose checks. He is Asian, in his fifties or sixties, with greying hair and a smiling, weather-worn face.

As I prep his finger for the glucose stick, he tells me, “Do you want to know a secret?”

“What is it?” I ask, politely.

“I have a bad liver. My doctor gives me medication to take every day. But here’s the secret. I can make the medication last longer if I only take it when my skin is yellow. See?” He presses on his skin so that it turns pale. “That’s how I check.”

He tells me this with the confidence of a man who does not expect to be challenged. After all, I am a young Asian woman, fresh out of college. In most traditional Asian cultures, the young do not correct the elderly. I probe delicately, with deference and respect.

“Why do you want to make the medication last longer?” I ask.

“To save money, of course!” the man exclaims.

He looks at me incredulously. However, after some more questions, I find out that he is financially secure. Why then, is he concerned about money? I don’t need to ask to understand. My parents and grandparents are similar. After World War II, conflict continued in East Asia for decades. The people became frugal by necessity. When my grandfather was eighteen, he fled to Taiwan with nothing but the clothes on his back. He instilled in my father the mindset of thrift, bordering on cheapness, that everything must be used until it falls apart. Clothing should be worn and handed down until it became threadbare. No grain of rice should be wasted.

I can see that same frugality in this gentleman.

“Maybe there is a reason that the doctor wants you to take the medication every day,” I suggest as I wrap a bandaid around his finger.

“Ayy, they just want my money,” he says with a smile. Then he becomes doubtful. “And I feel fine.”

I attempt to nudge him along.

“It wouldn’t hurt to ask your doctor.”

Then I tell him that his blood glucose is normal. He smiles and shrugs and raises his eyebrows as if to say, See? Everything is fine. He thanks me. I watch him leave and hope that I had said the right things.

Today’s Daily Post Writing Prompt: Yellow

Ten Minutes

“It’s amazing how much you can learn about someone in ten minutes of casual conversation.”

The doors swing open. I bustle through, the tails of my short white coat fluttering behind me. It is my first day as a medical student in this hospital and I’ve been sent to see Mrs. “W”. I look around, a little lost, and hope that I’ve finally found the right floor. The nurse sitting at the desk looks up. Her eyes are very large and very blue.

“Welcome to the floor!” she says, with amazing cheer for seven o’clock in the morning.

I freeze in my tracks.

“Thank you,” I say.

Her wide, blue eyes continue to stare at me. Her lips are smiling, curved in a pink, plastic smile like a Barbie doll. I feel like an unwelcome intruder, a lost third-year medical student playing doctor and invading the daily churn and flow of the unit. And so I continue, stuttering nervously over my words.

“I-I’m here to see a patient.”

“Thank you for coming to see our patient!” she says.

Her enthusiasm remains unflagging. I introduce myself and mumble a few somewhat coherent sentences like Where-Is-Room-12? and something about the weather and Have-A-Nice-Day! Eventually I find my way to the patient.

Mrs. W is a thin 60-something-year-old woman with COPD (causing shortness of breath) and venous insufficiency (which causes severe pain in her legs) who, well, also does a bit of cocaine every now and then. While she came to the hospital for breathing problems, her primary complaint is her leg pain. She has been scheduled for an outpatient vascular surgery clinic. But until then, she must live with the pain. We discuss the benefits of walking.

“I know it’s hard to exercise in the hospital, but walking would really help,” I tell her.

“Maybe if I had someone to walk with,” she says.

And so that’s how it began. In the afternoon after rounds, I return to her room. We walk two laps around the unit together. She is surprisingly steady on her feet, requiring no assistance, though occasionally she leans against the wall and stops due to pain. And in those ten short minutes, I learn about her. She tells me about her children, two of whom live hundreds of miles away and are too busy to see her. The third is jobless and lives with her at home and helps her “sometimes” around the house. She tells me of how she used to work long days as a single mother to support the family. And how she struggled to quit smoking and finally stopped a few years ago, but hasn’t been able to quit the cocaine.

“I tell myself it’s the last time every time,” she says. “Then I have a bad day and I just do it. I know I gotta stop ’cause it’s bad for my heart, but deep down, I guess I’m not ready yet.”

It’s amazing how much you can learn about someone in ten minutes of casual conversation.

The next day, I am unable to return to her room until much later in the day. She nearly tumbles out of bed when she sees me.

“I thought you forgot about me,” she says.

“Of course not!” I reply.

After I ask about her day, she asks about mine. I share a little about my life. The astounding (but ever shrinking!) number of years of future education that I had yet to traverse. That no, I am not married, but I am in a long-term relationship with my boyfriend. And I tell her some silly things, like how I had ran through the pounding rain that morning and dropped my phone in a puddle. And somehow, it still works!

The nurses notice. They exclaim over how great Mrs. W looks. The exercise put some color in her cheeks, they say. And she is walking so well and so steady on her feet! They dote on her with genuine affection and when they turn to look at me, I can see their gratitude.

We manage to walk three laps.

“Maybe tomorrow we can walk four,” Mrs. W says with a smile.

When I leave that day, the blue-eyed nurse stops me in the hall.

“Thank you for walking with our patient!” she says, with her ever-present cheer.

This time, I smile back.

Today’s Daily Post Writing Prompt: Ten