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Thriving in the Face of Treatment Resistance

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Margaret Chisolm, MD, shares a model of flourishing that moves beyond symptomatic treatment and helps patients find meaningful lives even when their medications do not work.

CME: Take the CME Post-Test for this episode

Published On: 03/21/2022

Duration: 15 minutes, 24 seconds

Related Articles: Mental Illness and Flourishing,” The Carlat Psychiatry Report, March 2022

Chris Aiken, MD, Kellie Newsome, PMHNP, and Margaret Chisolm, MD, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

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What do you do when medications don’t work? Try another? And another? Or do you change the conversation, and help patients find a life worth living in the face of symptoms that don’t remit? Today, we speak with Margaret Chisolm to find some answers. 

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief and the coauthor of the new textbook Prescribing Psychotropics. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

“We don’t need to equate pharmacologic futility with hopelessness. We have to maintain some sense with the patient of “we’ll get you through this,” though it may not be with pills. We need to be honest with the patient and set realistic expectations. The goals need to shift away from disease transformation and toward disease management. Whatever we do in terms of medication, we need to talk about how you’re coping with it.”

KELLIE NEWSOME: That was Joe Goldberg. We interviewed him in 2020 as he was putting the finishing touches on his new textbook out – Practical Psychopharmacology. The book is full of expert tips on the science of psych meds, but Joe reminded us that most of our patients need more than medication, and many of them don’t get help from medications at all. 

Treatment resistance is common. We spend a lot of our time helping patients manage their lives when their meds aren’t working. Sometimes it’s tempting to refer them to psychotherapy, but what if they don’t have the time or resources to take it on? Or what if psychotherapy doesn’t work any better than meds? We’re still in the same boat. 

CHRIS AIKEN: Joe mentioned the “placebo effect” in that quote. And he went on to explain that this mysterious tincture has some ingredient that we have not fully captured. The placebo is not a sugar pill, and it’s not a hopeful illusion – mind over matter or wishful thinking. The placebo is what we do to bring out the healthier side of the patient, their strength, their resilience, and their ability to persevere through hardship. 

Whatever you call it, this “placebo” is a big part of treatment. In adults, about 30% of the recovery you see on an antidepressant is placebo. In severe depression, it’s much less, about 10%, and in mild depression it’s more, 50%. In children, it’s about 40%.

KELLIE NEWSOME: A quick aside. Maybe you’ve heard that antidepressants don’t work in children – and it’s true that fewer than 10% of the trials in kids were positive. Or maybe you recall the media headlines claiming that antidepressants don’t work. Well, there’s some truth to that. Antidepressants clearly work in severe depression, but they have a much harder time proving that these meds work in children or in mild depression because the placebo response in these groups is so high.

CHRIS AIKEN: And when it comes to sleep medications, the placebo is even stronger than the med. When your patient takes zolpidem – Ambien – they’ll fall asleep 30 minutes faster on average. But Ambien only makes them fall asleep 10 minutes faster – the other 20 minutes from the placebo – which is baked into the Ambien tablet.

KELLIE NEWSOME: Yea but it’s only baked in if you do your job right. The FDA does not regulate the production or delivery of the placebo, and it’s consistency is known to vary from practitioner to practitioner. This brings us to a well-kept secret in psychiatric research. When they run trials with a lot of different psychiatrists delivering the treatment, they usually don’t parse out the results for each clinician because doing so might be embarrassing if – say – you were the psychiatrist who always managed to have a very low placebo response. But when they compare results among different providers, they usually see some outliers on both sides. Some practitioners generate high placebo responses, and some inspire such poor placebo responses that their patients rarely get better even when they take the medication.

CHRIS AIKEN: But we’re all in the same boat. We could all improve when it comes to our role in the placebo response. I’m always looking for psychiatrists who can help me grow in this area, who’ve given a lot of thought to what helps patients heal beyond treating their symptoms. One of those psychiatrists is Margaret Chisolm. Dr. Chisolm has written a book for patients, From Survive to Thrive: Living Your Best Life with Mental Illness, and she spoke to us about how she helps patients live meaningful lives even when we can’t bring all their symptoms to remission.

KELLIE NEWSOME: But first, a preview of our CME quiz for this podcast.

According to an epidemiologic study from 2019, which of these pairs are among the four pathways to flourishing and well-being in life?

A. Gratitude and community

B. Work and education

C. Financial stability and physical activity

D. Family support and physical health

CHRIS AIKEN: Some people define health as the absence of disease, but I get the sense that you have a more detailed model of health and wellbeing. 

Dr. Chisolm: Yeah, well a lot of my work has been informed by Tyler VanderWheele’s Model of Flourishing and he wrote a JAMA paper in 2019 called “Reimagining Health.” Basically, he also is making explicit things that we know implicitly, which is that leading your best life has several domains. 

The ones that he’s talked about, which philosophers have talked about for a long time when considering what it means to lead a good life, are happiness, life satisfaction, mental and physical health, meaning and purpose, character and virtue, and close social relationships. He also talks about financial stability or material security. So you know those are the components which most people would agree to lead a good life. 

And what Tyler has done is … he’s an epidemiologist who studies these large longitudinal data sets and his area of expertise is causal inference, so he’s drawn causal links from these data sets between the pathways of flourishing and these domains of flourishing, and he’s found the four pathways to flourishing are – not surprisingly to all of us who work with patients – family, community. He specifically talks about the religious community because obviously in epidemiologic data sets that’s something they ask most people about. So the four pathways to flourishing are family, community, work, and education. He specifically talks about religious community which is what the epidemiologic data sets often ask people about.

CHRIS AIKEN: Tell us more about each of those domains. 

Dr. Chisolm: So the family is sort of obvious to us, right? When somebody is getting better from their illness or needs support in getting better from their illness it’s really important to getting well and staying well to have the support of family and have those relationships; somebody that cares about you, somebody that you know you matter to if your dead or alive it’s gonna matter to them, really important. It’s important for people you know recovering from addiction to have that support of family members. Often they’ve burned bridges so they have to rebuild those with family members. 

But we encourage our patients just as we consider them from each of the four perspectives; we consider each of our patients from these four pathways. You know what is the strength of their family ties? What ties do they have to the community? Do they need to be in AA or NA for a supportive community? Would it benefit them to reconnect to their faith community? 

Then we also look at the strength of their work. Do they have meaning and purpose in their work? Is there someone at work that depends on them? In terms of drug addiction, I’m addiction medicine certified so I keep going back to addiction, but in terms of drug addiction, thinking about the positive reinforcement that work is and how it can compete with drug use if somebody is having meaning and purpose and a pleasurable experience socially at work. 

And then the fourth pathway is education. You know it’s important for people to be able to read and to be able to learn whether it’s formal learning or informal learning to be able to engage with the world that they live in brings meaning and purpose. It’s an area where people can meet other people obviously, so that’s the fourth pathway that we like to strengthen. 

So thinking about the four perspectives and what’s needed to kind of get somebody on the path to recovery from their acute problems that brought them into treatment and then thinking about those pathways moving forward, what can we do to help them reach their greatest potential. And these pathways are relevant even to somebody who has a disease, right? If they have schizophrenia their trajectory might be a little different from what had been expected, you know somebody who got ill when they were at MIT, for instance, might have been on one trajectory, now they have this very serious illness, and even though they might not be on the same trajectory they can still lead a flourishing life; they can still lead a good life, but it’s usually through these pathways, having supportive family, being part of the community, getting meaningful work, and attaining the educational level they desire and are capable of.

CHRIS AIKEN: I can see how this could be helpful for people who haven’t had a full recovery with medications. Do you talk about these 4 pathways explicitly with them?

Dr. Chisolm: Yeah, absolutely. I mean, first of all I would never give up hope that somebody is not gonna get better with newer medications and with time, but I do think that as somebody is  recovering or in a very slow state of recovery from an acute major mental illness they can still work on these pathways and draw meaning from their relationships whether it’s a partial hospital program or through a you know job training program or through a sheltered workplace or with engaging with the NAOMI community, there are many ways that people can lead meaningful lives even when they’re ill.

CHRIS AIKEN: I’d guess that if they work on those pathways, their medication might work better.

Dr. Chisolm: Absolutely, well now I think that you would be more likely (You know I don’t have a study about this, but I’m just talking off the top of my head), but I do think you would be more likely to take your medication if you were leading a good life and there was somebody waiting for you at work and if you didn’t take your medication you might not be well enough to go to work. 

You know the thing about the life story perspective is that it’s retrospective; it’s looking backwards in time. These pathways are really looking forward in time and thinking about what are somebody’s goals? What’s going to keep them moving forward getting a little better each day in some aspect of their life? Maybe their hallucinations and delusions aren’t going to get any better maybe, but the quality of life can still keep improving as they form close social relationships, take care of their physical health, and find some meaning and purpose in a job or other activities. You know I just think being satisfied with a non flourishing life, a languishing life is acceptable for any of our patients. I would not accept that for any of my patients.

KELLIE NEWSOME: Dr. Chisolm speaks more about flourishing in our online interview, and also shares a practical model of mental illness that has guided practice for many years at the institution she practices at: Johns Hopkins Department of Psychiatry, where she is a professor of psychiatry and Vice Chair for Education. Margaret Chisolm’s new book is From Survive to Thrive: Living Your Best Life with Mental Illness. She also has a book for professionals, Systematic Psychiatric Evaluation: A Step-by-Step Guide to Applying The Perspectives of Psychiatry.

And now for the word of the day…. Allopregnanolone

CHRIS AIKEN: It’s the psych med you’ve probably never prescribed: Allopregnanolone, better known by it’s chemical name brexanolone, or brand name Zulresso, the first medication to gain FDA approval for postpartum depression. We’re guessing you haven’t prescribed it because it costs $34,000 and has to be delivered through an overnight IV. Brexanolone may be regulated as a medication, but it’s really a synthetic version of a naturally occurring hormone that the body makes on its own by converting progesterone. This hormone takes a precipitous fall after childbirth, shaking up the GABA receptors and contributing to postpartum depression. 

When I say “synthetic hormone” I mean it’s a bit like levo-thyroxine, the popular thyroid supplement that goes by the brand name Synthroid.  Thyroxine is the natural form and levo-thyroxine is the synthetically made isomer that you can prescribe. Likewise, pregnenolone is the natural form, and allopregnanolone – aka brexanolone – is the synthetic isomer.

KELLIE NEWSOME: But wait – a lot of my patients take pregnenolone from alternative medicine doctors. Is that the same thing as this $34,000 brexanolone?

CHRIS AIKEN: Yes. It has a different route – oral vs. intravenous – and a different dose – but for clinical purposes it’s the same basic chemical. All these names are a bit confusing, and to take the confusion one step further there’s another one on the horizon – Zuranolone – it’s an oral version of brexanolone that is close to FDA approval for major depression. Join us next week for a primer on this neurosteroid that may soon be branded as an antidepressant.

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