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Our top 6 tips for managing nausea on psych meds, and a queasy tale of a tenacious problem to watch for when your patients who get nauseous: Conditioned taste aversion.

Published On: 8/9/2021

Duration: 18 minutes, 16 seconds

Transcript:

Today we’ll bring you 6 ways to manage nausea on psych meds, and weave a queasy tale of a tenacious problem to watch for when your patients who get nauseous: Conditioned taste aversion.

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

Nausea. We think we know what it is, but as Drs Balaban and Yates put it in a recent review of the symptom, “Although the expulsion of gastric contents through vomiting is easy to recognize, the sequelae of physiological responses that precede this response are less clear-cut.” The article goes on to describe 30 definitions of this queasy symptom.

Nausea did not make much of a splash in early medical texts – the Egyptians hardly mentioned it. It wasn’t until the ancient Greeks attempted to conquer the seas with the newly discovered science of shipbuilding that the word crops up. Sailing the high seas came with an unpleasant side effect: sea-sickness. The Greeks called this affliction nausea, and those of you sea-fearing types might recognize the nautical root in that word. 

Today, we think of nausea as a protective mechanism, one that mother nature, evolution or your higher power put in place to help us quickly expunge spoiled food and toxins before they settle in and do greater damage. But most medicines can also register this toxic alert, and if you don’t take care to manage nausea in your patients it may cause them to avoid their medication entirely and possibly anything else they ate around the time they took it. That’s because nausea causes an a unique unconscious effect called conditioned taste aversion.

Conditioned taste aversion

Dr. Aiken: When you put your hand on a hot stove, a reflex causes you to pull it away immediately. That reflex is strong – but it doesn’t generalize – you’re not going to run away from stoves for the rest of your life because of one bad experience. But if you keep getting burned on the stove, you might develop conditioned avoidance of stoves or even the entire kitchen. That kind of conditioning is at the heart of behavior science, and we see it with all kinds of aversive symptoms – from pain to anxiety to rejection.

But in the 1950’s psychologist John Garcia changed all that. Just as the innovations in shipbuilding brought nausea to the awareness of Greek physicians, it was a menacing invention of the 20th century that sparked the discovery of a neural mechanism unique to nausea: The nuclear bomb.

Working in the U.S. Naval Radiological Defense Lab in San Francisco, California, Dr. Garcia was trying to figure out how radiation affected the brains of rats when he noticed something unusual. When placed the rats in a radiation chamber, they happily drank water from plastic bottles before being hit with a nausea-inducing dose of radiation. But after the radiation, these same rats would refuse to drink from those same plastic bottles, but would still drink water from glass containers. Dr. Garcia speculated that the rats somehow associated the plasticky taste of the water with the radiation, and in a series of other experiments he discovered that it was not the radiation itself but the nausea it induced that caused them to avoid the water. To figure that out, he used a medication that causes nausea in a lot of our patients: Lithium. Garcia found he could create an aversion to any food by injecting a rat with lithium an hour or so after they ate it.

Kellie Newsome: That sounds like standard conditioning, so how did that shake up behavior science?

Dr. Aiken: Behaviorists thought that conditioning was a slow process that required repeated exposures for the aversive linking to set in. But Garcia claimed to have induced strong conditioning after only one exposure. Also, behaviorists believed that you could pair anything with an aversive stimulus to create conditioned avoidance – Pavlov started with the bell that got dogs salivating, but sights, scents, and touch could just as easily be paired. But when it came to nausea, Garcia claimed that only taste and smell could be paired. When he tried to pair visual images with the nausea, they didn’t click. And for patients, that’s a mixed blessing.

Kellie Newsome: What this means is that your patient is not likely to develop conditioned taste aversion to their medication, because most medications don’t have any taste or smell unless they are flavored like some of our liquids or orally disintegrating tablets are. Asenapine – Saphris – has a cherry flavor, and lamotrigine ODT comes in peppermint and cherry flavors. What happens instead with medication-related nausea is that patients may avoid anything they ate before taking a nausea-inducing medication like lithium or an SSRI. 

Dr. Aiken: Here’s an example. After starting lithium on a patient, he told me he was no longer able to eat pesto. What had happened was he had taken lithium after eating pesto, and the nausea that then ensued got linked to the pesto. Pesto has a strong flavor, and the brain is more likely to link strong flavors with nausea. This was disconcerting for him because pesto had been one of his favorite foods, and it’s a pretty healthy one to boot.

Kellie Newsome: What happened then?

Dr. Aiken: He eventually got over it. Conditioned taste aversion can last weeks to years, but it can be overcome through reverse conditioning. Take the pesto. If he continued to push himself to eat the pesto and didn’t get nauseas after eating it then the conditioning will go away. Which in his case it did because – thankfully – nausea is usually a temporary side effect to starting lithium. And he is able to enjoy pesto again.

Kellie Newsome: Patients may not think to tell you about conditioned taste aversion, but it’s fairly common after nausea-inducing meds. The more severe the nausea, or the stronger the flavor of the food, the worse the aversion. Oncologists are particularly tuned into conditioned taste aversion because food avoidance can become quite a problem after repeated bouts of nausea-inducing chemotherapy or radiation. They will advise patients not to eat foods they enjoy before chemotherapy – but just how long should they wait? That varies. In most experiments, an hour is danger zone – anything eaten within an hour before nausea is likely to get conditioned – which makes sense if you think about how long the digestion process takes. But even foods eaten a few hours before the nausea can become paired, and the stronger the flavor the more likely the pairing. 

That has led to a novel solution that’s sometimes used in chemotherapy called the scapegoat effect. In the 1980’s, psychologists discovered that they could trick the brain into avoiding strongly flavored candy, like coconut or rootbeer lifesavers, by giving the candy along with a typical meal before chemotherapy. When the nausea set in, the candy was the scapegoat, and the patients developed an aversion to the lifesavers – which is preferable to avoiding chicken, bread, or vegetables. 

Dr. Aiken: John Garcia’s experiments were met with skepticism in the 1950’s, but after 10 or 20 years of contentious back and forth in scientific journals he convinced the field that conditioned avoidance does take a different route with nausea. But that wasn’t his only battle. Dr. Garcia was also one of the first scientists to raise alarms about the dangers of nuclear testing. While working at the radiation lab, he noticed that animals downwind from nuclear test sites were dying en masse. He testified before congress and flew with John F Kennedy to Vienna to discuss the problem with Soviet leaders – efforts that culminated in the Nuclear Test Ban Treaty of 1963.

By the time of Dr. Garcia’s death in 2012, conditioned taste avoidance was an established part of mainstream science. It has even been used to explain anorexia nervosa. Estrogen can cause nausea, in fact it is one of the reasons that pregnancy makes women nauseas – that and human chorionic gonadotropin. The theory with anorexia is that the rise of estrogen in early puberty causes young girls to associate various foods with nausea, and that this conditioned taste avoidance spreads as they go through puberty, eventually causing them to avoid all foods. This isn’t just a theory – there’s actually a lot of research backing it up – but it’s probably just one of many mechanisms that can lead to anorexia nervosa.

Kellie Newsome: OK enough history and science. Now for the practical tips. In this month’s Carlat Report we feature a research update that ranks all of the modern-day antidepressants by their tendency to cause GI side effects – everything from constipation to diarrhea to nausea. And today, we bring you six ways to manage nausea on psych meds:

1. Extended release formulations. Anything that irritates the stomach lining can cause nausea, so extended release versions usually have a lower risk of nausea. This strategy is particularly helpful with lithium, lamotrigine, Depakote, carbamazepine, and paroxetine, all of which have some evidence to reduce nausea with their XR formulations.
2. ODTs. Orally disintegrating tablets are another option as these largely bypass the stomach – these are available for many medications including the antipsychotics aripiprazole, asenapine, clozapine, olanzapine, and risperidone; the mood stabilizer lamotrigine; as well as mirtazapine, alprazolam, clonazepam, zolpidem/Ambien, and the dementia medication donepezil. And all of those ODTS are now generic – in fact the only branded ODTs we are aware of are the stimulants. Amphetamine comes as the branded Adzenys XR ODT and methylphenidate as Cotempla XR ODT.
3. Change the medication. Some psychiatric medications have anti-nausea properties built into them. Benzos have antinausea properties, particularly lorazepam/Ativan which is FDA approved for chemotherapy-induced nausea. Mirtazapine is often used by GI doctors to treat nausea, which it accomplishes through serotonin 5HT3 antagonism. Olanzapine also treats nausea through this mechanism. 
4. Add an anti-nausea med. Ondansetron is a 5HT3 antagonist that is FDA approved for nausea, and although we know of no studies using ondansetron to treat nausea on psych meds it is certainly reasonable to try. In our experience we’ve had good results. Ondansetron is pretty safe and well tolerated with the main side effect of constipation. But it also has psychiatric benefits that may be relevant to your patients. In small controlled trials ondansetron has improved binge eating, alcoholism, and obsessive compulsive disorder. 
5. Promethazine (Phenergan) can also treat nausea, but keep in mind this anti-emetic was originally developed as an antipsychotic, and it can cause tardive dyskinesia. For that reason, we use it as a last resort in our patients because each antipsychotic exposure increases the risk of TD, and with the broad transdiagnostic use of these agents we know that many of our patients are eventually going to be treated with an antipsychotic.
6. Ginger. Finally, we often start with nature’s cure – ginger capsules. Most patients prefer this as they don’t want to add a medicine to treat the side effects of another one. Ginger has been used since ancient times to treat nausea, and modern controlled trials have confirmed that the anti-emetic properties of ginger in nausea due to various causes including chemotherapy, pregnancy, post-operative nausea, and motion sickness. Psychiatrist Rajnish Mago recommends ginger for nausea on psychotropics, and we’ve had good experience with it as well. Ginger capsules are considered safe by the FDA, and it’s a standard treatment for nausea in Europe. 

Here’s how to use it. Have your patient take a ginger capsule on an empty stomach about an hour before dinner or another large meal. The dose is t 1,000-2,000mg, and there are lots of good brands out there – we use NOW and Nature’s Way. Next, wait an hour for the ginger to dissolve and take effect. Ginger treats nausea through several mechanism – it increases gastric tone, blocks cholinergic M3 receptors, and – like ondansetron – blocks serotonin 5-HT3 in the GI tract.  After waiting an hour, have the patient eat a large meal – this will coat their stomach so the medication will be less irritating to the stomach lining. Then, have them take the medication right after the large meal. So the order is ginger first, then a large meal, then the medication on top of all that.

There’s one hole in this strategy – if they do develop nausea, they may have conditioned avoidance to whatever food they ate. But this doesn’t worry us, because remember conditioned avoidance will affect anything they ate up to a few hours before the nausea comes on, so there’s really no way around that – patients are going to eat something for diner – and this strategy at least reduces the nausea and hence the likelihood of conditioning.

Dr. Aiken: Nausea is not a dangerous side effect, but it’s a highly aversive one. The unconscious process of conditioned avoidance may not apply to medications – which are tasteless and odorless – but nausea can still cause patients to reject medications early on when they consciously associate the nausea with the new med. Treat nausea early and aggressively to prevent this – if you don’t, it has a way of spreading, because nausea can become a self-perpetuating cycle. With most medications, the nausea only occurs in the first few weeks and then goes away. In our experience, nausea is a big problem with lithium, the SSRIs, vortioxetine/Trintellix, and pramipexole, which is used off-label for bipolar depression and treatment resistant depression. To prevent the problem, I usually start these meds very low and raise them slowly, such as raising lithium by 300mg every week, or starting vortioxetine at 5mg every other day.

And now for the word of the day….Nightmare 

Kellie Newsome: How do you tell the difference between normal human sadness and clinical depression, everyday anxiety and generalized anxiety disorder, just another bad dream and… A diagnosable nightmare. You turn to the DSM of course, the source of all things pathologic. And the big blue book does contain a medical definition of nightmares, which are “extended, extremely dysphoric, and well-remembered dreams that usually involve efforts to avoid threats to survival or security or physical integrity.” Fear is the predominant emotion in these dreams, although anger, shame and sadness may also rear their ugly heads. Nightmare Disorder is a DSM-5 sleep disorder where nightmares happen frequently, cause distress or impairment, and are not better explained by another psychiatric disorder or a drug or medication. But who gets nightmare disorder? And how does it cause distress? Barry Krakow has spent his career studying and treating nightmares, and we’ll interview him in next Monday’s podcast.

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